Substituted 1,2,4-triazoles as intermediates in the synthesis of TYK2 inhibitors

ABSTRACT

Described herein are compounds, for example, 1,2,4-triazole-substituted N-heteroaryl amines, that are useful in treating a TYK2-mediated disorder. In some embodiments, the TY-K2-mediated disorder is an autoimmune disorder, an inflammatory disorder, a proliferative disorder, an endocrine disorder, a neurological disorder, or a disorder associated with transplantation.

CROSS-REFERENCE

This patent application is a continuation of U.S. patent applicationSer. No. 17/713,646, filed Apr. 5, 2022; which is a continuation of U.S.patent application Ser. No. 17/243,508, filed Apr. 28, 2021; which is acontinuation of U.S. patent application Ser. No. 16/938,183, filed Jul.24, 2020; which is a continuation of International Patent ApplicationNo. PCT/US2019/057485, filed Oct. 22, 2019; which claims the benefit of,and priority to, U.S. Provisional Application No. 62/749,003, filed Oct.22, 2018; U.S. Provisional Application No. 62/756,942, filed Nov. 7,2018; U.S. Provisional Application No. 62/839,459, filed Apr. 26, 2019;U.S. Provisional Application No. 62/875,449, filed Jul. 17, 2019; U.S.Provisional Application No. 62/893,721, filed Aug. 29, 2019; and U.S.Provisional Application No. 62/907,354, filed Sep. 27, 2019 each ofwhich is incorporated herein by reference in their entirety.

FIELD OF THE INVENTION

Described herein are compounds, methods of making such compounds,pharmaceutical compositions and medicaments comprising such compounds,and methods of using such compounds for inhibiting nonreceptortyrosine-protein kinase 2 (“TYK2”), also known as Tyrosine kinase 2.

BACKGROUND OF THE INVENTION

TYK2 is a non-receptor tyrosine kinase member of the Janus kinase (JAKs)family of protein kinases. The mammalian JAK family consists of fourmembers, TYK2, JAK1, JAK2, and JAK3. JAK proteins, including TYK2, areintegral to cytokine signaling. TYK2 associates with the cytoplasmicdomain of type I and type II cytokine receptors, as well as interferontypes I and III receptors, and is activated by those receptors uponcytokine binding. Cytokines implicated in TYK2 activation includeinterferons (e.g. IFN-α, IFN-β, IFN-κ, IFN-δ, IFN-ε, IFN-τ, IFN-ω, andIFN-ζ (also known as limitin), and interleukins (e.g. IL-4, IL-6, IL-10,IL-11, IL-12, IL-13, L-22, IL-23, IL-27, IL-31, oncostatin M, ciliaryneurotrophic factor, cardiotrophin 1, cardiotrophin-like cytokine, andLIF). The activated TYK2 then goes on to phosphorylate further signalingproteins such as members of the STAT family, including STAT1, STAT2,STAT4, and STAT6.

TYK2 activation by IL-23, has been linked to inflammatory bowel disease(IBD), Crohn's disease, and ulcerative colitis. A genome-wideassociation study of 2,622 individuals with psoriasis identifiedassociations between disease susceptibility and TYK2. Knockout ortyrphostin inhibition of TYK2 significantly reduces both IL-23 andIL-22-induced dermatitis.

TYK2 also plays a role in respiratory diseases such as asthma, chronicobstructive pulmonary disease (COPD), lung cancer, and cystic fibrosis.Goblet cell hyperplasia (GCH) and mucous hypersecretion is mediated byIL-13-induced activation of TYK2, which in turn activates STAT6.

Decreased TYK2 activity leads to protection of joints from collagenantibody-induced arthritis, a model of human rheumatoid arthritis.Mechanistically, decreased Tyk2 activity reduced the production ofTh1/Th17-related cytokines and matrix metalloproteases, and other keymarkers of inflammation.

TYK2 knockout mice showed complete resistance in experimental autoimmuneencephalomyelitis (EAE, an animal model of multiple sclerosis (MS)),with no infiltration of CD4 T cells in the spinal cord, as compared tocontrols, suggesting that TYK2 is essential to pathogenic CD4-mediateddisease development in MS. This corroborates earlier studies linkingincreased TYK2 expression with MS susceptibility. Loss of functionmutation in TYK2, leads to decreased demyelination and increasedremyelination of neurons, further suggesting a role for TYK2 inhibitorsin the treatment of MS and other CNS demyelination disorders.

TYK2 is the sole signaling messenger common to both IL-12 and IL-23.TYK2 knockout reduced methylated BSA injection-induced footpadthickness, imiquimod-induced psoriasis-like skin inflammation, anddextran sulfate sodium or 2,4,6-trinitrohenzene sulfonic acid-inducedcolitis in mice.

Joint linkage and association studies of various type I IFN signalinggenes with systemic lupus erythematosus (SLE, an autoimmune disorder),showed a strong, and significant correlation between loss of functionmutations to TYK2 and decreased prevalence of SLE in families withaffected members. Genome-wide association studies of individuals withSLE versus an unaffected cohort showed highly significant correlationbetween the TYK2 locus and SLE.

TYK2 has been shown to play an important role in maintaining tumorsurveillance and TYK2 knockout mice showed compromised cytotoxic T cellresponse, and accelerated tumor development. However, these effects werelinked to the efficient suppression of natural killer (NK) and cytotoxicT lymphocytes, suggesting that TYK2 inhibitors would be highly suitablefor the treatment of autoimmune disorders or transplant rejection.Although other JAK family members such as JAK3 have similar roles in theimmune system, TYK2 has been suggested as a superior target because ofits involvement in fewer and more closely related signaling pathways,leading to fewer off-target effects.

Studies in T-cell acute lymphoblastic leukemia (T-ALL) indicate thatT-ALL is highly dependent on IL-10 via TYK2 via STAT1-mediated signaltransduction to maintain cancer cell survival through upregulation ofanti-apoptotic protein BCL2. Knockdown of TYK2, but not other JAK familymembers, reduced cell growth. Specific activating mutations to TYK2 thatpromote cancer cell survival include those to the FERM domain (G36D,S47N, and R425H), the JH2 domain (V731I), and the kinase domain (E957Dand R1027H). However, it was also identified that the kinase function ofTYK2 is required for increased cancer cell survival, as TYK2 enzymesfeaturing kinase-dead mutations (M978Y or M978F) in addition to anactivating mutation (E957D) resulted in failure to transform.

Thus, selective inhibition of TYK2 has been suggested as a suitabletarget for patients with IL-10 and/or BCL2-addicted tumors, such as 70%of adult T-cell leukemia cases. TYK2 mediated STAT3 signaling has alsobeen shown to mediate neuronal cell death caused by amyloid-β (Aβ)peptide. Decreased TYK2 phosphorylation of STAT3 following Aβadministration lead to decreased neuronal cell death, and increasedphosphorylation of STAT3 has been observed in postmortem brains ofAlzheimer's patients.

Inhibition of JAK-STAT signaling pathways is also implicated in hairgrowth, and the reversal of the hair loss associated with alopeciaareata.

Accordingly, compounds that inhibit the activity of TYK2 are beneficial,especially those with selectivity over JAK2. Such compounds shoulddeliver a pharmacological response that favorably treats one or more ofthe conditions described herein without the side-effects associated withthe inhibition of JAK2.

Accordingly there is a need to provide novel inhibitors having moreeffective or advantageous pharmaceutically relevant properties, likeselectivity over other JAK kinases (especially JAK2).

BRIEF SUMMARY OF THE INVENTION

Disclosed herein is a compound of Formula (XII), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof:

wherein:

-   -   Ring B is cycloalkyl, heterocycloalkyl, aryl, heteroaryl;    -   R¹⁶ is —C(═O)NR¹R², —C(═N—CN)NR¹R², —P(═O)R¹R², or —C(═O)R¹¹;    -   R¹ and R² are independently hydrogen, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,        C₁-C₆aminoalkyl, C₂-C₆alkenyl, or C₂-C₆alkynyl;    -   R³ is hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl, or        C₁-C₆deuteroalkyl;    -   R⁴ is hydrogen, deuterium, halogen, —CN, —OR^(b), —SR^(b),        —S(═O)R^(a), —S(═O)₂R^(a), —NO₂, —NR^(c)R^(d), —NHS(═O)₂R^(a),        —S(═O)₂NR^(c)R^(d), —C(═O)R^(a), —OC(═O)R^(a), —C(═O)OR^(b),        —OC(═O)OR^(b), —C(═O)NR^(c)R^(d), —OC(═O)NR^(c)R^(d),        —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a), —NR^(b)C(═O)OR^(b),        —P(═O)R^(b)R^(b), C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl,        C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₂-C₆alkenyl, or        C₂-C₆alkynyl;    -   or R³ and R⁴ are taken together to form an optionally        substituted ring;    -   L is a bond or —C(═O)—;    -   Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;        each optionally substituted with one or more R^(A);    -   each R^(A) is independently deuterium, halogen, —CN, —OR^(b),        —SR^(b), —S(═O)R^(a), —S(═O)₂R^(a), —NO₂, —NR^(c)R^(d),        —NHS(═O)₂R^(a), —S(═O)₂NR^(c)R^(d), —C(═O)R^(a), —OC(═O)R^(a),        —C(═O)OR^(b), —OC(═O)OR^(b), —C(═O)NR^(c)R^(d),        —OC(═O)NR^(c)R^(d), —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a),        —NR^(b)C(═O)OR^(b), C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,        C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl,        or heteroaryl; wherein each alkyl, alkenyl, alkenyl, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl is independently        optionally substituted with one or more oxo, deuterium, halogen,        —CN, —OR^(b), —NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b),        —C(═O)NR^(c)R^(d), C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   or two R^(A) on the same carbon are taken together to form an        oxo;    -   or -L-Ring A is absent;    -   each X is independently —CR^(x)— or —N—;    -   each R^(x) is independently hydrogen, deuterium, halogen, —CN,        —OR^(b), —SR^(b), —S(═O)R^(a), —S(═O)₂R^(a), —NO₂, —NR^(c)R^(d),        —NHS(═O)₂R^(a), —S(═O)₂NR^(c)R^(d), —C(═O)R^(a), —OC(═O)R^(a),        —C(═O)OR^(b), —OC(═O)OR^(b), —C(═O)NR^(c)R^(d),        —OC(═O)NR^(c)R^(d), —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a),        —NR^(b)C(═O)OR^(b), C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,        C₂-C₆alkenyl, or C₂-C₆alkynyl;    -   R⁵ is halogen, —CN, —OR⁸, —SR⁸, —S(═O)R⁷, —S(═O)₂R⁷, —NO₂,        —NR⁹R¹⁰, —NR⁸S(═O)R⁷, —NR⁸S(═O)₂R⁷, —S(═O)₂NR⁹R¹⁰, —C(═N—CN)R⁷,        —C(═O)R⁷, 13 OC(═N—CN)R⁷, —OC(—O)R⁷, —C(═N—CN)OR⁸, —C(═O)OR⁸,        —OC(═N—CN)OR⁸, —OC(═O)OR⁸, —C(═N—CN)NR⁹R¹⁰, —C(═O)NR⁹R¹⁰,        —OC(═N—CN)NR⁹R¹⁰, —OC(═O)NR⁹R¹⁰, —NR⁸C(═N—CN)NR⁹R¹⁰,        —NR⁸C(═O)NR⁹R¹⁰, —NR⁸C(═N—CN)R⁷, —NR⁸C(═N—OH)R⁷,        —NR⁸C(═N—CN)OR⁸, —NR⁸C(═O)OR⁸, —NR⁸S(═O)(═NR⁸)R⁷, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,        C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl,        alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one or        more oxo, deuterium, halogen, —CN, —OR^(b), —NR^(c)R^(d),        —C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,        C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,        cycloalkyl, heterocycloalkyl, aryl, heteroaryl,        C₁-C₆alkyl(cycloalkyl), C₁-C₆alkyl(heterocycloalkyl),        C₁-C₆alkyl(aryl), or C₁-C₆alkyl(heteroaryl); wherein each alkyl,        alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one or        more oxo, deuterium, halogen, —CN, —OR^(b), —NR^(c)R^(d),        —C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆alkyl, or        C₁-C₆haloalkyl;    -   R⁷ is C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl,        C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,        cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each        alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one or        more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH₂, —C(═O)Me,        —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   each R⁸ is independently hydrogen, CN, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,        C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl,        alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one or        more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH₂, —C(═O)Me,        —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   R⁹ and R¹⁰ are independently hydrogen, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,        C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl,        alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one or        more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH₂, —C(═O)Me,        —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, C₁-C₆deuteroalkyl,        C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆hydroxydeuteroalkyl,        cycloalkyl, or heterocycloalkyl;    -   or R⁹ and R¹⁰ are taken together with the nitrogen atom to which        they are attached to form a heterocycloalkyl optionally        substituted with one or more oxo, deuterium, halogen, —CN, —OH,        —OMe, —NH₂, —C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or        C₁-C₆haloalkyl;    -   or R⁸ and R⁹ are taken together with the atoms to which they are        attached to form a heterocycloalkyl optionally substituted with        one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH₂,        —C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   R¹¹ is C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl,        C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,        cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each        alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one or        more R^(11a);    -   each R^(11a) is independently deuterium, halogen, —CN, —OR^(b),        —SR^(b), —S(═O)R^(a), —S(═O)₂R^(a), —NO₂, —NR^(c)R^(d),        —NHS(═O)₂R^(a), —S(═O)₂NR^(c)R^(d), —C(═O)R^(a), —OC(═O)R^(a),        —C(═O)OR^(b), —OC(═O)OR^(b), —C(═O)NR^(c)R^(d),        —OC(═O)NR^(c)R^(d), —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a),        —NR^(b)C(═O)OR^(b), C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,        C₂-C₆alkenyl, or C₂-C₆alkenyl;    -   each R^(a) is independently C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,        C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl,        or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl is independently        optionally substituted with one or more oxo, deuterium, halogen,        —CN, —OH, —OMe, —NH₂, —C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl,        or C₁-C₆haloalkyl;    -   each R^(b) is independently hydrogen, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,        C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl,        alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one or        more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH₂, —C(═O)Me,        —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   each R^(c) and R^(d) is independently hydrogen, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,        C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl,        alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one or        more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH₂, —C(═O)Me,        —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   or R^(c) and R^(d) are taken together with the nitrogen atom to        which they are attached to form a heterocycloalkyl optionally        substituted with one or more oxo, deuterium, halogen, —CN, —OH,        —OMe, —NH₂, —C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or        C₁-C₆haloalkyl.

Also disclosed herein is a compound of Formula (XIII), or apharmaceutically acceptable salt, stereoisomer, or solvate thereof:

wherein:

-   -   Ring B is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;    -   R³ is hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl, or        C₁-C₆deuteroalkyl;    -   R⁴ is hydrogen, deuterium, halogen, —CN, —OR^(b), —SR^(b),        —S(═O)R^(a), —S(═O)₂R^(a), —NO₂, —NR^(c)R^(d), —NHS(═O)₂R^(a),        —S(═O)₂NR^(c)R^(d), —C(═O)R^(a), —OC(═O)R^(a), —C(═O)OR^(b),        —OC(═O)OR^(b), —C(═O)NR^(c)R^(d), —OC(═O)NR^(c)R^(d),        —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a), —NR^(b)C(═O)OR^(b),        —P(═O)R^(b)R^(b), C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl,        C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₂-C₆alkenyl, or        C₂-C₆alkynyl;    -   or R³ and R⁴ are taken together to form an optionally        substituted ring;    -   L is a bond or —C(═O)—;    -   Ring A is cycloalkyl, heterocycloalkyl, aryl or heteroaryl; each        optionally substituted with one or more R^(A);    -   each R^(A) is independently deuterium, halogen, —CN, —OR^(b),        —SR^(b), —S(═O)R^(a), —S(═O)₂R^(a), —NO₂, —NR^(c)R^(d),        —NHS(═O)₂R^(a), —S(═O)₂NR^(c)R^(d), —C(═O)R^(a), —OC(═O)R^(a),        —C(═O)OR^(b), —OC(═O)OR^(b), —C(═O)NR^(c)R^(d),        —OC(═O)NR^(c)R^(d), —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a),        —NR^(b)C(═O)OR^(b), C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,        C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl,        or heteroaryl; wherein each alkyl, alkenyl, alkenyl, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl is independently        optionally substituted with one or more oxo, deuterium, halogen,        —CN, —OR^(b), —NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b),        —C(═O)NR^(c)R^(d), C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   or two R^(A) on the same carbon are taken together to form an        oxo;    -   or -L-Ring A is absent;    -   each X is independently —CR^(x)— or —N—;    -   each R^(x) is independently hydrogen, deuterium, halogen, —CN,        —OR^(b), —SR^(b), —S(═O)R^(a), —S(═O)₂R^(a), —NO₂, —NR^(c)R^(d),        —NHS(═O)₂R^(a), —S(═O)₂NR^(c)R^(d), —C(═O)R^(a), —OC(═O)R^(a),        —C(═O)OR^(b), —OC(═O)OR^(b), —C(═O)NR^(c)R^(d),        —OC(═O)NR^(c)R^(d), —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a),        —NR^(b)C(═O)OR^(b), C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,        C₂-C₆alkenyl, or C₂-C₆alkynyl;    -   R⁵ is halogen, —CN, —OR⁸, —SR⁸, —S(═O)R⁷, —S(═O)₂R⁷, —NO₂,        —NR⁹R¹⁰, —NR⁸S(═O)R⁷, —NR⁸S(═O)₂R⁷, —S(═O)₂NR⁹R¹⁰, —C(═N—CN)R⁷,        —C(═O)R⁷, 13 OC(═N—CN)R⁷, —OC(—O)R⁷, —C(═N—CN)OR⁸, —C(═O)OR⁸,        —OC(═N—CN)OR⁸, —OC(═O)OR⁸, —C(═N—CN)NR⁹R¹⁰, —C(═O)NR⁹R¹⁰,        —OC(═N—CN)NR⁹R¹⁰, —OC(═O)NR⁹R¹⁰, —NR⁸C(═N—CN)NR⁹R¹⁰,        —NR⁸C(═O)NR⁹R¹⁰, —NR⁸C(═N—CN)R⁷, —NR⁸C(═N—OH)R⁷, —NR⁸C(═O)R⁷,        —NR⁸C(═N—CN)OR⁸, —NR⁸C(═O)OR⁸, —NR⁸S(═O)(═NR⁸)R⁷, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,        C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl,        alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one or        more oxo, deuterium, halogen, —CN, —OR^(b), —NR^(c)R^(d),        —C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,        C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,        cycloalkyl, heterocycloalkyl, aryl, heteroaryl,        C₁-C₆alkyl(cycloalkyl), C₁-C₆alkyl(heterocycloalkyl),        C₁-C₆alkyl(aryl), or C₁-C₆alkyl(heteroaryl); wherein each alkyl,        alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one or        more oxo, deuterium, halogen, —CN, —OR^(b), —NR^(c)R^(d),        —C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆alkyl, or        C₁-C₆haloalkyl;    -   R⁷ is C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl,        C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,        cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each        alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one or        more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH₂, —C(═O)Me,        —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   each R⁸ is independently hydrogen, CN, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,        C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl,        alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one or        more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH₂, —C(═O)Me,        —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   R⁹ and R¹⁰ are independently hydrogen, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,        C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl,        alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one or        more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH₂, —C(═O)Me,        —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, C₁-C₆deuteroalkyl,        C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆hydroxydeuteroalkyl,        cycloalkyl, or heterocycloalkyl;    -   or R⁹ and R¹⁰ are taken together with the nitrogen atom to which        they are attached to form a heterocycloalkyl optionally        substituted with one or more oxo, deuterium, halogen, —CN, —OH,        —OMe, —NH₂, —C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or        C₁-C₆haloalkyl;    -   or R⁸ and R⁹ are taken together with the atoms to which they are        attached to form a heterocycloalkyl optionally substituted with        one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH₂,        —C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   R¹¹ is C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl,        C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,        cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each        alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one or        more R^(11a);    -   each R^(11a) is independently deuterium, halogen, —CN, —OR^(b),        —SR^(b), —S(═O)R^(a), —S(═O)₂R^(a), —NO₂, —NR^(c)R^(d),        —NHS(═O)₂R^(a), —S(═O)₂NR^(c)R^(d), —C(═O)R^(a), —OC(═O)R^(a),        —C(═O)OR^(b), —OC(═O)OR^(b), —C(═O)NR^(c)R^(d),        —OC(═O)NR^(c)R^(d), —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a),        —NR^(b)C(═O)OR^(b), C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,        C₂-C₆alkenyl, or C₂-C₆alkenyl;    -   each R^(a) is independently C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,        C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl,        or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl is independently        optionally substituted with one or more oxo, deuterium, halogen,        —CN, —OH, —OMe, —NH₂, —C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl,        or C₁-C₆haloalkyl;    -   each R^(b) is independently hydrogen, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,        C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl,        alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one or        more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH₂, —C(═O)Me,        —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   each R^(c) and R^(d) is independently hydrogen, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,        C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl,        alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one or        more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH₂, —C(═O)Me,        —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   or R^(c) and R^(d) are taken together with the nitrogen atom to        which they are attached to form a heterocycloalkyl optionally        substituted with one or more oxo, deuterium, halogen, —CN, —OH,        —OMe, —NH₂, —C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or        C₁-C₆haloalkyl.

Also disclosed herein is a pharmaceutical composition comprising atherapeutically effective amount of the compound disclosed herein, or apharmaceutically acceptable salt, stereoisomer, or solvate thereof, anda pharmaceutically acceptable excipient.

Also disclosed herein is a method of inhibiting a TYK2 enzyme in apatient or biological sample comprising contacting said patient orbiological sample with a compound disclosed herein, or apharmaceutically acceptable salt, stereoisomer, or solvate thereof.

Also disclosed herein is a method of treating a TYK2-mediated disordercomprising administering to a patient in need thereof a compounddisclosed herein, or a pharmaceutically acceptable salt, stereoisomer,or solvate thereof. In some embodiments, the TYK2-mediated disorder isan autoimmune disorder, an inflammatory disorder, a proliferativedisorder, an endocrine disorder, a neurological disorder, or a disorderassociated with transplantation. In some embodiments, the disorder isassociated with type I interferon, IL-10, IL-12, or IL-23 signaling.

DETAILED DESCRIPTION OF THE INVENTION Definitions

As used herein and in the appended claims, the singular forms “a,” “an,”and “the” include plural referents unless the context clearly dictatesotherwise. Thus, for example, reference to “an agent” includes aplurality of such agents, and reference to “the cell” includes referenceto one or more cells (or to a plurality of cells) and equivalentsthereof known to those skilled in the art, and so forth. When ranges areused herein for physical properties, such as molecular weight, orchemical properties, such as chemical formulae, all combinations andsubcombinations of ranges and specific embodiments therein are intendedto be included. The term “about” when referring to a number or anumerical range means that the number or numerical range referred to isan approximation within experimental variability (or within statisticalexperimental error), and thus the number or numerical range, in someinstances, will vary between 1% and 15% of the stated number ornumerical range. The term “comprising” (and related terms such as“comprise” or “comprises” or “having” or “including”) is not intended toexclude that in other certain embodiments, for example, an embodiment ofany composition of matter, composition, method, or process, or the like,described herein, “consist of” or “consist essentially of” the describedfeatures.

As used in the specification and appended claims, unless specified tothe contrary, the following terms have the meaning indicated below.

“Aliphatic chain” refers to a linear chemical moiety that is composed ofonly carbons and hydrogens. In some embodiments, the aliphatic chain issaturated. In some embodiments, the aliphatic chain is unsaturated. Insome embodiments, the unsaturated aliphatic chain contains oneunsaturation. In some embodiments, the unsaturated aliphatic chaincontains more than one unsaturation. In some embodiments, theunsaturated aliphatic chain contains two unsaturations. In someembodiments, the unsaturated aliphatic chain contains one double bond.In some embodiments, the unsaturated aliphatic chain contains two doublebonds.

“Alkyl” refers to an optionally substituted straight-chain, oroptionally substituted branched-chain saturated hydrocarbon monoradicalhaving from one to about ten carbon atoms, or from one to six carbonatoms. Examples include, but are not limited to, methyl, ethyl,n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl,2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl,2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl,4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl,4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl,2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl,isopentyl, neopentyl, tert-amyl and hexyl, and longer alkyl groups, suchas heptyl, octyl, and the like. Whenever it appears herein, a numericalrange such as “C₁-C₆ alkyl” means that the alkyl group consists of 1carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbonatoms or 6 carbon atoms, although the present definition also covers theoccurrence of the term “alkyl” where no numerical range is designated.In some embodiments, the alkyl is a C₁-C₁₀ alkyl, a C₁-C₉ alkyl, a C₁-C₈alkyl, a C₁-C₇ alkyl, a C₁-C₆ alkyl, a C₁-C₅ alkyl, a C₁-C₄ alkyl, aC₁-C₃ alkyl, a C₁-C₂ alkyl, or a C₁ alkyl. Unless stated otherwisespecifically in the specification, an alkyl group is optionallysubstituted, for example, with oxo, halogen, amino, nitrile, nitro,hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl,heteroaryl, and the like. In some embodiments, the alkyl is optionallysubstituted with oxo, halogen, —CN, —CF₃, —OH, —OMe, —NH₂, or —NO₂. Insome embodiments, the alkyl is optionally substituted with oxo, halogen,—CN, —CF₃, —OH, or —OMe. In some embodiments, the alkyl is optionallysubstituted with halogen.

“Alkenyl” refers to an optionally substituted straight-chain, oroptionally substituted branched-chain hydrocarbon monoradical having oneor more carbon-carbon double-bonds and having from two to about tencarbon atoms, more preferably two to about six carbon atoms. The groupmay be in either the cis or trans conformation about the double bond(s),and should be understood to include both isomers. Examples include, butare not limited to, ethenyl (—CH═CH₂), 1-propenyl (—CH₂CH═CH₂),isopropenyl [—C(CH₃)═CH₂], butenyl, 1,3-butadienyl and the like.Whenever it appears herein, a numerical range such as “C₂-C₆ alkenyl”means that the alkenyl group may consist of 2 carbon atoms, 3 carbonatoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although thepresent definition also covers the occurrence of the term “alkenyl”where no numerical range is designated. In some embodiments, the alkenylis a C₂-C₁₀ alkenyl, a C₂-C₉ alkenyl, a C₂-C₈ alkenyl, a C₂-C₇ alkenyl,a C₂-C₆ alkenyl, a C₂-C₅ alkenyl, a C₂-C₄ alkenyl, a C₂-C₃ alkenyl, or aC₂ alkenyl. Unless stated otherwise specifically in the specification,an alkenyl group is optionally substituted, for example, with oxo,halogen, amino, nitrite, nitro, hydroxyl, haloalkyl, alkoxy, aryl,cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In someembodiments, an alkenyl is optionally substituted with oxo, halogen,—CN, —CF₃, —OH, —OMe, —NH₂, or —NO₂. In some embodiments, an alkenyl isoptionally substituted with oxo, halogen, —CN, —CF₃, —OH, or —OMe. Insome embodiments, the alkenyl is optionally substituted with halogen.

“Alkynyl” refers to an optionally substituted straight-chain oroptionally substituted branched-chain hydrocarbon monoradical having oneor more carbon-carbon triple-bonds and having from two to about tencarbon atoms, more preferably from two to about six carbon atoms.Examples include, but are not limited to, ethynyl, 2-propynyl,2-butynyl, 1,3-butadiynyl and the like. Whenever it appears herein, anumerical range such as “C₂-C₆ alkynyl” means that the alkynyl group mayconsist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbonatoms or 6 carbon atoms, although the present definition also covers theoccurrence of the term “alkynyl” where no numerical range is designated.In some embodiments, the alkynyl is a C₂-C₁₀ alkynyl, a C₂-C₉ alkynyl, aC₂-C₈ alkynyl, a C₂-C₇ alkynyl, a C₂-C₆ alkynyl, a C₂-C₅ alkynyl, aC₂-C₄ alkynyl, a C₂-C₃ alkynyl, or a C₂ alkynyl. Unless stated otherwisespecifically in the specification, an alkynyl group is optionallysubstituted, for example, with oxo, halogen, amino, nitrile, nitro,hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl,heteroaryl, and the like. In some embodiments, an alkynyl is optionallysubstituted with oxo, halogen, —CN, —CF₃, —OH, —OMe, —NH₂, or —NO₂. Insome embodiments, an alkynyl is optionally substituted with oxo,halogen, —CN, —CF₃, —OH, or —OMe. In some embodiments, the alkynyl isoptionally substituted with halogen.

“Alkylene” refers to a straight or branched divalent hydrocarbon chain.Unless stated otherwise specifically in the specification, an alkylenegroup may be optionally substituted, for example, with oxo, halogen,amino, nitrite, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl,heterocycloalkyl, heteroaryl, and the like. In some embodiments, analkylene is optionally substituted with oxo, halogen, —CN, —CF₃, —OH,—OMe, —NH₂, or —NO₂. In some embodiments, an alkylene is optionallysubstituted with oxo, halogen, —CN, —CF₃, —OH, or —OMe. In someembodiments, the alkylene is optionally substituted with halogen.

“Alkoxy” refers to a radical of the formula —OR_(a) where R_(a) is analkyl radical as defined. Unless stated otherwise specifically in thespecification, an alkoxy group may be optionally substituted, forexample, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl,alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. Insome embodiments, an alkoxy is optionally substituted with oxo, halogen,—CN, —CF₃, —OH, —OMe, —NH₂, or —NO₂. In some embodiments, an alkoxy isoptionally substituted with oxo, halogen, —CN, —CF₃, —OH, or —OMe. Insome embodiments, the alkoxy is optionally substituted with halogen.

“Aminoalkyl” refers to an alkyl radical, as defined above, that issubstituted by one or more amines. In some embodiments, the alkyl issubstituted with one amine. In some embodiments, the alkyl issubstituted with one, two, or three amines. Hydroxyalkyl include, forexample, aminomethyl, aminoethyl, aminopropyl, aminobutyl, oraminopentyl. In some embodiments, the hydroxyalkyl is aminomethyl.

“Aryl” refers to a radical derived from a hydrocarbon ring systemcomprising hydrogen, 6 to 30 carbon atoms and at least one aromaticring. The aryl radical may be a monocyclic, bicyclic, tricyclic ortetracyclic ring system, which may include fused (when fused with acycloalkyl or heterocycloalkyl ring, the aryl is bonded through anaromatic ring atom) or bridged ring systems. In some embodiments, thearyl is a 6- to 10-membered aryl. In some embodiments, the aryl is a6-membered aryl. Aryl radicals include, but are not limited to, arylradicals derived from the hydrocarbon ring systems of anthrylene,naphthylene, phenanthrylene, anthracene, azulene, benzene, chrysene,fluoranthene, fluorene, as-indacene, s-indacene, indane, indene,naphthalene, phenalene, phenanthrene, pleiadene, pyrene, andtriphenylene. In some embodiments, the aryl is phenyl. Unless statedotherwise specifically in the specification, an aryl may be optionallysubstituted, for example, with halogen, amino, nitrile, nitro, hydroxyl,alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl,heterocycloalkyl, heteroaryl, and the like. In some embodiments, an arylis optionally substituted with halogen, methyl, ethyl, —CN, —CF₃, —OH,—OMe, —NH₂, or —NO₂. In some embodiments, an aryl is optionallysubstituted with halogen, methyl, ethyl, —CN, —CF₃, —OH, or —OMe. Insonic embodiments, the aryl is optionally substituted with halogen.

“Cycloalkyl” refers to a stable, partially or fully saturated,monocyclic or polycyclic carbocyclic ring, which may include fused (whenfused with an aryl or a heteroaryl ring, the cycloalkyl is bondedthrough a non-aromatic ring atom) or bridged ring systems.Representative cycloalkyls include, but are not limited to, cycloalkylshaving from three to fifteen carbon atoms (C₃-C₁₅ cycloalkyl), fromthree to ten carbon atoms (C₃-C₁₀ cycloalkyl), from three to eightcarbon atoms (C₃-C₈ cycloalkyl), from three to six carbon atoms (C₃-C₆cycloalkyl), from three to five carbon atoms (C₃-C₅ cycloalkyl), orthree to four carbon atoms (C₃-C₄ cycloalkyl). In some embodiments, thecycloalkyl is a 3- to 6-membered cycloalkyl. In some embodiments, thecycloalkyl is a 5- to 6-membered cycloalkyl. Monocyclic cycloalkylsinclude, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls or carbocyclesinclude, for example, adamantyl, norbornyl, decatinyl,bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decalin, trans-decalin,bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane,bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane, and7,7-dimethyl-bicyclo[2.2.1]heptanyl. Partially saturated cycloalkylsinclude, for example cyclopentenyl, cyclohexenyl, cycloheptenyl, andcyclooctenyl. Unless stated otherwise specifically in the specification,a cycloalkyl is optionally substituted, for example, with oxo, halogen,amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl,alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. Insome embodiments, a cycloalkyl is optionally substituted with oxo,halogen, methyl, ethyl, —CN, —CF₃, —OH, —OMe, —NH₂, or —NO₂. In someembodiments, a cycloalkyl is optionally substituted with oxo, halogen,methyl, ethyl, —CN, —CF₃, —OH, or —OMe. In some embodiments, thecycloalkyl is optionally substituted with halogen.

“Deuteroalkyl” refers to an alkyl radical, as defined above, that issubstituted by one or more deuterium atoms. In some embodiments, thealkyl is substituted with one deuterium atom. In some embodiments, thealkyl is substituted with one, two, or three deuterium atoms. In someembodiments, the alkyl is substituted with one, two, three, four, five,or six deuterium atoms. Deuteroalkyl includes, for example, CD₃, CH₂D,CHD₂, CH₂CD₃, CD₂CD₃, CHDCD₃, CH₂CH₂D, or CH₂CHD₂. In some embodiments,the deuteroalkyl is CD₃.

“Haloalkyl” refers to an alkyl radical, as defined above, that issubstituted by one or more halogen atoms. In some embodiments, the alkylis substituted with one, two, or three halogen atoms. In someembodiments, the alkyl is substituted with one, two, three, four, five,or six halogen halogens. Haloalkyl includes, for example,trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl,2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bronco-2-fluoropropyl,1,2-dibromoethyl, and the like. In some embodiments, the haloalkyl istrifluoromethyl.

“Halo” or “halogen” refers to bromo, chloro, fluoro or iodo. In someembodiments, halogen is fluoro or chloro. In some embodiments, halogenis fluoro.

“Heteroalkyl” refers to an alkyl group in which one or more skeletalatoms of the alkyl are selected from an atom other than carbon, e.g.,oxygen, nitrogen (e.g., —NH—, —N(alkyl)—), sulfur, or combinationsthereof. A heteroalkyl is attached to the rest of the molecule at acarbon atom of the heteroalkyl. In one aspect, a heteroalkyl is a C₁-C₆heteroalkyl wherein the heteroalkyl is comprised of 1 to 6 carbon atomsand one or more atoms other than carbon, e.g., oxygen, nitrogen (e.g.—NH—, —N(alkyl)—), sulfur, or combinations thereof wherein theheteroalkyl is attached to the rest of the molecule at a carbon atom ofthe heteroalkyl. Examples of such heteroalkyl are, for example,—CH₂OCH₃, —CH₂CH₂OCH₃, —CH₂CH₂OCH₂CH₂OCH₃, or —CH(CH₃)OCH₃. Unlessstated otherwise specifically in the specification, a heteroalkyl isoptionally substituted for example, with oxo, halogen, amino, nitrile,nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl,cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In someembodiments, a heteroalkyl is optionally substituted with oxo, halogen,methyl, ethyl, —CN, —CF₃, —OH, —OMe, —NH₂, or —NO₂. In some embodiments,a heteroalkyl is optionally substituted with oxo, halogen, methyl,ethyl, —CN, —CF₃, —OH, or —OMe. In some embodiments, the heteroalkyl isoptionally substituted with halogen.

“Hydroxyalkyl” refers to an alkyl radical, as defined above, that issubstituted by one or more hydroxyls. In some embodiments, the alkyl issubstituted with one hydroxyl. In some embodiments, the alkyl issubstituted with one, two, or three hydroxyls. Hydroxyalkyl include, forexample, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, orhydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl.

“Heterocycloalkyl” refers to a stable 3- to 24-membered partially orfully saturated ring radical comprising 2 to 23 carbon atoms and fromone to 8 heteroatoms selected from the group consisting of nitrogen,oxygen, phosphorous and sulfur. In some embodiments, theheterocycloalkyl comprises 1 or 2 heteroatoms selected from nitrogen andoxygen. Unless stated otherwise specifically in the specification, theheterocycloalkyl radical may be a monocyclic, bicyclic, tricyclic ortetracyclic ring system, which may include fused (when fused with anaryl or a heteroaryl ring, the heterocycloalkyl is bonded through anon-aromatic ring atom) or bridged ring systems; and the nitrogen,carbon or sulfur atoms in the heterocycloalkyl radical may be optionallyoxidized; the nitrogen atom may be optionally quaternized.Representative heterocycloalkyls include, but are not limited to,heterocycloalkyls having from two to fifteen carbon atoms (C₂-C₁₅heterocycloalkyl), from two to ten carbon atoms (C₂-C₁₀heterocycloalkyl), from two to eight carbon atoms (C₂-C₈heterocycloalkyl), from two to six carbon atoms (C₂-C₆heterocycloalkyl), from two to five carbon atoms (C₂-C₅heterocycloalkyl), or two to four carbon atoms (C₂-C₄ heterocycloalkyl).In some embodiments, the heterocycloalkyl is a 3- to 6-memberedheterocycloalkyl. In some embodiments, the cycloalkyl is a 5- to6-membered heterocycloalkyl. Examples of such heterocycloalkyl radicalsinclude, but are not limited to, aziridinyl, azetidinyl, dioxolanyl,thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl,imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl,octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl,2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl,piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl,thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl,thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl,1,1-dioxo-thiomorpholinyl, 1,3-dihydroisobenzofuran-1-yl,3-oxo-1,3-dihydroisobenzofuran-1-yl, methyl-2-oxo-1,3-dioxol-4-yl, and2-oxo-1,3-dioxol-4-yl. The term heterocycloalkyl also includes all ringforms of the carbohydrates, including but not limited to, themonosaccharides, the disaccharides and the oligosaccharides. It isunderstood that when referring to the number of carbon atoms in aheterocycloalkyl, the number of carbon atoms in the heterocycloalkyl isnot the same as the total number of atoms (including the heteroatoms)that make up the heterocycloalkyl (i.e. skeletal atoms of theheterocycloalkyl ring). Unless stated otherwise specifically in thespecification, a heterocycloalkyl is optionally substituted, forexample, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl,alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl,heteroaryl, and the like. In some embodiments, a heterocycloalkyl isoptionally substituted with oxo, halogen, methyl, ethyl, —CN, —CF₃, —OH,—OMe, —NH₂, or —NO₂. In some embodiments, a heterocycloalkyl isoptionally substituted with oxo, halogen, methyl, ethyl, —CN, —CF₃, —OH,or —OMe. In some embodiments, the heterocycloalkyl is optionallysubstituted with halogen.

“Heteroalkyl” refers to an alkyl group in which one or more skeletalatoms of the alkyl are selected from an atom other than carbon, e.g.,oxygen, nitrogen (e.g. —NH—, —N(alkyl)—), sulfur, or combinationsthereof. A heteroalkyl is attached to the rest of the molecule at acarbon atom of the heteroalkyl. In one aspect, a heteroalkyl is a C₁-C₆heteroalkyl. Unless stated otherwise specifically in the specification,a Heteroalkyl is optionally substituted, for example, with oxo, halogen,amino, nitrite, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl,alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. Insome embodiments, a heteroalkyl is optionally substituted with oxo,halogen, methyl, ethyl, —CN, —CF₃, —OH, —OMe, —NH₂, or —NO₂. In someembodiments, a heteroalkyl is optionally substituted with oxo, halogen,methyl, ethyl, —CN, —CF₃, —OH, or —OMe. In some embodiments, theheteroalkyl is optionally substituted with halogen.

“Heteroaryl” refers to a 5- to 14-membered ring system radicalcomprising hydrogen atoms, one to thirteen carbon atoms, one to sixheteroatoms selected from the group consisting of nitrogen, oxygen,phosphorous and sulfur, and at least one aromatic ring. The heteroarylradical may be a monocyclic, bicyclic, tricyclic or tetracyclic ringsystem, which may include fused (when fused with a cycloalkyl orheterocycloalkyl ring, the heteroaryl is bonded through an aromatic ringatom) or bridged ring systems; and the nitrogen, carbon or sulfur atomsin the heteroaryl radical may be optionally oxidized; the nitrogen atommay be optionally quaternized. In some embodiments, the heteroaryl is a5- to 10-membered heteroaryl. In some embodiments, the heteroaryl is a5- to 6-membered heteroaryl. Examples include, but are not limited to,azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl,benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl,benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl,benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl,benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl(benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl,carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl,furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl,isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl,isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl,oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl,1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl,phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl,pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl,quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl,tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl,triazinyl, and thiophenyl (i.e., thienyl). Unless stated otherwisespecifically in the specification, a heteroaryl is optionallysubstituted, for example, with halogen, amino, nitrile, nitro, hydroxyl,alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl,heterocycloalkyl, heteroaryl, and the like. In some embodiments, aheteroaryl is optionally substituted with halogen, methyl, ethyl, —CN,—CF₃, —OH, —OMe, —NH₂, or —NO₂. In some embodiments, a heteroaryl isoptionally substituted with halogen, methyl, ethyl, —CN, —CF₃, —OH, or—OMe. In some embodiments, the heteroaryl is optionally substituted withhalogen.

The terms “treat,” “prevent,” “ameliorate,” and “inhibit,” as well aswords stemming therefrom, as used herein, do not necessarily imply 100%or complete treatment, prevention, amelioration, or inhibition. Rather,there are varying degrees of treatment, prevention, amelioration, andinhibition of which one of ordinary skill in the art recognizes ashaving a potential benefit or therapeutic effect. In this respect, thedisclosed methods can provide any amount of any level of treatment,prevention, amelioration, or inhibition of the disorder in a mammal. Forexample, a disorder, including symptoms or conditions thereof, may bereduced by, for example, about 100%, about 90%, about 80%, about 70%,about 60%, about 50%, about 40%, about 30%, about 20%, or about 10%.Furthermore, the treatment, prevention, amelioration, or inhibitionprovided by the methods disclosed herein can include treatment,prevention, amelioration, or inhibition of one or more conditions orsymptoms of the disorder, e.g., cancer or an inflammatory disease. Also,for purposes herein, “treatment,” “prevention,” “amelioration,” or“inhibition” encompass delaying the onset of the disorder, or a symptomor condition thereof.

The terms “effective amount” or “therapeutically effective amount,” asused herein, refer to a sufficient amount of a compound disclosed hereinbeing administered which will relieve to some extent one or more of thesymptoms of the disease or condition being treated, e.g., cancer or aninflammatory disease. In some embodiments, the result is a reductionand/or alleviation of the signs, symptoms, or causes of a disease, orany other desired alteration of a biological system. For example, an“effective amount” for therapeutic uses is the amount of the compositioncomprising a compound disclosed herein required to provide a clinicallysignificant decrease in disease symptoms. In some embodiments, anappropriate “effective” amount in any individual case is determinedusing techniques, such as a dose escalation study.

As used herein, the term “TYK2-mediated” disorders, diseases, and/orconditions as used herein means any disease or other deleteriouscondition in which TYK2 or a mutant thereof is known to play a role.Accordingly, another embodiment relates to treating or lessening theseverity of one or more diseases in which TYK2, or a mutant thereof, isknown to play a role. Such TYK2-mediated disorders include but are notlimited to autoimmune disorders, inflammatory disorders, proliferativedisorders, endocrine disorders, neurological disorders and disordersassociated with transplantation.

Compounds

Described herein are compounds that are useful in treating aTYK2-mediated disorder. In some embodiments, the TYK2-mediated disorderis an autoimmune disorder, an inflammatory disorder, a proliferativedisorder, an endocrine disorder, a neurological disorder, or a disorderassociated with transplantation.

Disclosed herein is a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof:

wherein:

-   -   Z is a bond, —CR^(Z) ₂—, or —(CR^(Z) ₂)₂—;    -   each R^(Z) is independently hydrogen, deuterium, halogen, —CN,        —OR^(b), —NR^(c)R^(d), C₁-C₆alkyl, C₁-C₆haloalkyl, or        C₁-C₆deuteroalkyl;    -   R¹ and R² are independently hydrogen, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,        C₁-C₆aminoalkyl, C₂-C₆alkenyl, or C₂-C₆alkynyl;    -   R³ is hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl, or        C₁-C₆deuteroalkyl;    -   R⁴ is hydrogen, deuterium, halogen, —CN, —OR^(b), —SR^(b),        —S(═O)R^(a), —S(═O)₂R^(a), —NO₂, —NR^(c)R_(d), —NHS(═O)₂R^(a),        —S(═O)₂NR^(c)R^(d), —C(═O)R^(a), —OC(═O)R^(a), —C(═O)OR^(b),        —OC(═O)OR^(b), —C(═O)NR^(c)R^(d), —OC(═O)NR^(c)R^(d),        —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a), —NR^(b)C(═O)OR^(b),        C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl,        C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₂-C₆alkenyl, or        C₂-C₆alkynyl;    -   or R³ and R⁴ are taken together to form an optionally        substituted ring;    -   L is a bond or —C(═O)—;    -   Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;        each optionally substituted with one or more R^(A);    -   each R^(A) is independently deuterium, halogen, —CN, —OR^(b),        —SR^(b), —S(═O)R^(a), —S(═O)₂R^(a), —NO₂, —NR^(c)R^(d),        —NHS(═O)₂R^(a), —S(═O)₂NR^(c)R^(d), —C(═O)R^(a), —OC(═O)R^(a),        —C(═O)OR^(b), —OC(═O)OR^(b), —C(═O)NR^(c)R^(d),        —OC(═O)NR^(c)R^(d), —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a),        —NR^(b)C(═O)OR^(b), C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,        C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl,        or heteroaryl; wherein each alkyl, alkenyl, alkenyl, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl is independently        optionally substituted with one or more oxo, deuterium, halogen,        —CN, —OR^(b), —NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b),        —C(═O)NR^(c)R^(d), C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   or two R^(A) on the same carbon are taken together to form an        oxo;    -   R⁵ is halogen, —CN, —OR⁸, —SR⁸, —S(═O)R⁷, —S(═O)₂R⁷, —NO₂,        —NR⁹R¹⁰, —NHS(═O)₂R⁷, —S(═O)₂NR⁹R¹⁰, C(═O)R⁷—OC(═O)R⁷,        —C(═O)OR⁸, —OC(═O)OR⁸, —C(═O)NR⁹R¹⁰, —OC(═O)NR⁹R¹⁰,        —NR⁸C(═O)NR⁹R¹⁰, —NR⁸C(═O)R⁷, —NR⁸C(═O)OR⁸, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,        C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl,        alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one or        more oxo, deuterium, halogen, —CN, —OR^(b), —NR^(c)R^(d),        —C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆alkyl, or        C₁-C₆haloalkyl;    -   R⁷ is C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl,        C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,        cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each        alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one or        more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH₂, —C(═O)Me,        —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   each R⁸ is independently hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,        C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl,        or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl is independently        optionally substituted with one or more oxo, deuterium, halogen,        —CN, —OH, —OMe, —NH₂, —C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl,        or C₁-C₆haloalkyl;    -   R⁹ and R¹⁰ are independently hydrogen, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,        C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl,        alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one or        more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH₂, —C(═O)Me,        —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   or R⁹ and R¹⁰ are taken together with the nitrogen atom to which        they are attached to form a heterocycloalkyl optionally        substituted with one or more oxo, deuterium, halogen, —CN, —OH,        —OMe, —NH₂, —C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or        C₁-C₆haloalkyl;    -   each R^(a) is independently C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,        C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl,        or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl is independently        optionally substituted with one or more oxo, deuterium, halogen,        —CN, —OH, —OMe, —NH₂, —C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl,        or C₁-C₆haloalkyl;    -   each R^(b) is independently hydrogen, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,        C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl,        alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one or        more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH₂, —C(═O)Me,        —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   each R^(c) and R^(d) is independently hydrogen, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,        C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl,        alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one or        more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH₂, —C(═O)Me,        —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   or R^(c) and R^(d) are taken together with the nitrogen atom to        which they are attached to form a heterocycloalkyl optionally        substituted with one or more oxo, deuterium, halogen, —CN, —OH,        —OMe, —NH₂, —C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or        C₁-C₆haloalkyl.

In some embodiments of a compound of Formula (I), L is a bond. In someembodiments of a compound of Formula (I), L is —C(═O)—.

In some embodiments of a compound of Formula (I), Ring A isheterocycloalkyl or heteroaryl; each optionally substituted with one ormore R^(A). In some embodiments of a compound of Formula (I), Ring A isa 5-membered heterocycloalkyl or a 5-membered heteroaryl; eachoptionally substituted with one or more R^(A). In some embodiments of acompound of Formula (I), Ring A is heteroaryl optionally substitutedwith one or more R^(A).

In some embodiments of a compound of Formula (I), each R^(A) isindependently deuterium, halogen, —CN, —OR^(b), —NR^(c)R^(d),C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d), —OC(═O)NR^(c)R^(d),C₁-C₆alkyl, C₁-C₆haloalkyl, or C₁-C₆deuteroalkyl. In some embodiments ofa compound of Formula (I), each R^(A) is independently deuterium,halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, or C₁-C₆deuteroalkyl. In someembodiments of a compound of Formula (I), each R^(A) is independentlyhalogen or C₁-C₆alkyl. In some embodiments of a compound of Formula (I),each R^(A) is independently C₁-C₆alkyl.

In some embodiments of a compound of Formula (I), R ⁴ is hydrogen,deuterium, halogen, —CN, —OR^(b), —NR^(c)R^(d), —C(═O)R^(a),—C(═O)OR^(b), —C(═O)NR^(c)R^(d), —OC(═O)NR^(c)R^(d), C₁-C₆alkyl,C₁-C₆haloalkyl, or C₁-C₆deuteroalkyl. In some embodiments of a compoundof Formula (I), R⁴ is hydrogen or —OR^(b). In some embodiments of acompound of Formula (I), R⁴ is —OR^(b). In some embodiments of acompound of Formula (I), R⁴ is hydrogen.

In some embodiments of a compound of Formula (I), the compound is ofFormula (Ia):

In some embodiments of a compound of Formula (I), the compound is ofFormula (Ib):

In some embodiments of a compound of Formula (I), (Ia), or (Ib), R³ ishydrogen or C₁-C₆alkyl. In some embodiments of a compound of Formula(I), (Ia), or (Ib), R³ is hydrogen.

In some embodiments of a compound of Formula (I), (Ia), or (Ib), Z is abond or —CH₂—. In some embodiments of a compound of Formula (I), (Ia),or (Ib), Z is —CH₂—. In some embodiments of a compound of Formula (I),(Ia), or (Ib), Z is a bond.

In some embodiments of a compound of Formula (I), (Ia), or (Ib), R¹ andR² are independently hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl, orC₁-C₆deuteroalkyl. In some embodiments of a compound of Formula (I),(Ia), or (Ib), R¹ and R² are independently hydrogen orC₁-C₆deuteroalkyl. In some embodiments of a compound of Formula (I),(Ia), or (Ib), R¹ is hydrogen. In some embodiments of a compound ofFormula (I), (Ia), or (Ib), R² is C₁-C₆alkyl or C₁-C₆deuteroalkyl. Insome embodiments of a compound of Formula (I), (Ia), or (Ib), R² isC₁-C₆deuteroalkyl.

In some embodiments of a compound of Formula (I), (Ia), or (Ib), R⁵ ishalogen, —CN, —OR⁸, —NR⁹R¹⁰, —C(═O)R⁷, —C(═O)OR⁸, —C(═O)NR⁹R¹⁰,—NR⁸C(═O)NR⁹R¹⁰, —NR⁸C(═O)R⁷, —NR⁸C(═O)OR⁸, C₁-C₆alkyl, C₁-C₆haloalkyl,C₁-C₆deuteroalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl,heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is independently optionallysubstituted with one or more oxo, deuterium, halogen, —CN, —OR^(b),NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆alkyl,or C₁-C₆haloalkyl.

In some embodiments of a compound of Formula (I), (Ia), or (Ib), R⁵ is—OR⁸, —NR⁹R¹⁰, —C(═O)R⁷, —C(═O)OR⁸, —C(═O)NR⁹R¹⁰, —NR⁸C(═O)NR⁹R¹⁰,—NR⁸C(═O)R⁷, —NR⁸C(═O)OR⁸, cycloalkyl, heterocycloalkyl, aryl, orheteroaryl; wherein each cycloalkyl, heterocycloalkyl, aryl, andheteroaryl is independently optionally substituted with one or more oxo,deuterium, halogen, —CN, —OR^(b), —NR^(c)R^(d), —C(═O)R^(a),—C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆alkyl, or C₁-C₆haloalkyl.

In some embodiments of a compound of Formula (I), (Ia), or (Ib), R⁵ is—OR⁸, —NR⁹R¹⁰, —NR⁸C(═O)R⁷, or aryl optionally substituted with one ormore oxo, deuterium, halogen, —CN, —OR^(b), —NR^(c)R^(d), —C(═O)R^(a),—C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆alkyl, or C₁-C₆haloalkyl.

In some embodiments of a compound of Formula (I), (Ia), or (Ib), R⁵ is—OR⁸, —NR⁹R¹⁰, NR⁸C(═O)R⁷, cycloalkyl, heterocycloalkyl, aryl, orheteroaryl; wherein each cycloalkyl, heterocycloalkyl, aryl, andheteroaryl is independently optionally substituted with one or more oxo,deuterium, halogen, —CN, —OR^(b), —NR^(c)R^(d), —C(═O)R^(a),—C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆alkyl, or C₁-C₆haloalkyl. In someembodiments of a compound of Formula (I), (Ia), or (Ib), R⁵ is—NR⁸C(═O)R⁷. In some embodiments of a compound of Formula (I), (Ia), or(Ib), R⁵ is aryl optionally substituted with one or more oxo, deuterium,halogen, —CN, —OR^(b), —NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b),—C(═O)NR^(c)R^(d), C₁-C₆alkyl, or C₁-C₆haloalkyl.

In some embodiments of a compound of Formula (I), (Ia), or (Ib), R⁷ isC₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, cycloalkyl,heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is independently optionallysubstituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe,—NH₂, —C(═O)ME, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl. Insome embodiments of a compound of Formula (I), (Ia), or (Ib), R⁷ isC₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, or cycloalkyl; whereineach alkyl, cycloalkyl, and heterocycloalkyl is independently optionallysubstituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe,—NH₂, —C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl. Insome embodiments of a compound of Formula (I), (Ia), or (Ib), R⁷ iscycloalkyl optionally substituted with one or more oxo, deuterium,halogen, —CN, —OH, —OMe, —NH₂, —C(═O)Me, —C(═O)OH, —C(═O)OMe,C₁-C₆alkyl, or C₁-C₆haloalkyl. In sonic embodiments of a compound ofFormula (I), (Ia), or (Ib), R⁷ is unsubstituted cycloalkyl.

In some embodiments of a compound of Formula (I), (Ia), or (Ib), R⁸ ishydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, cycloalkyl,heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is independently optionallysubstituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe,—NH₂, —C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl. Insome embodiments of a compound of Formula (I), (Ia), or (Ib), R⁸ ishydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, or cycloalkyl;wherein each alkyl, cycloalkyl, and heterocycloalkyl is independentlyoptionally substituted with one or more oxo, deuterium, halogen, —CN,—OH, —OMe, —NH₂, —C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, orC₁-C₆haloalkyl.

In some embodiments of a compound of Formula (I), (Ia), or (Ib), R⁹ andR¹⁰ are independently hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl,C₁-C₆deuteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroarylis independently optionally substituted with one or more oxo, deuterium,halogen, —CN, —OH, —OMe, —NH₂, —C(═O)Me, —C(═O)OH, —C(═O)OMe,C₁-C₆alkyl, or C₁-C₆haloalkyl. In some embodiments of a compound ofFormula (I), (Ia), or (Ib), R⁹ and R¹⁰ are independently hydrogen,C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, or cycloalkyl; whereineach alkyl, cycloalkyl, and heterocycloalkyl is independently optionallysubstituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe,—NH₂, —C(═O)Me, —C(═O)OH, —C(O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl.

Also disclosed herein is a compound of Formula (II) or (II′), or apharmaceutically acceptable salt, stereoisomer, or solvate thereof:

wherein:

-   -   R¹¹ is deuterium, halogen, —CN, —OR^(b), —SR^(b), —S(═O)R^(a),        —S(═O)₂R^(a), —NO₂, —NR^(c)R^(d), —NHS(═O)₂R^(a),        —S(═O)₂NR^(c)R^(d), —C(═O)R^(a), —OC(═O)R^(a), —C(═O)OR^(b),        —OC(═O)OR^(b), —C(═O)NR^(c)R^(d), —OC(═O)NR^(c)R^(d),        —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a), —NR^(b)C(═O)OR^(b),        C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl,        C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₂-C₆alkenyl, or        C₂-C₆alkynyl;    -   R¹ and R² are independently hydrogen, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,        C₁-C₆aminoalkyl, C₂-C₆alkenyl, or C₂-C₆alkynyl;    -   R³ is hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl, or        C₁-C₆deuteroalkyl;    -   R⁴ is hydrogen, deuterium, halogen, —CN, —OR^(b), —SR^(b),        —S(═O)R^(a), —S(═O)₂R^(a), —NO₂, —NR^(c)R_(d), —NHS(═O)₂R^(a),        —S(═O)₂NR^(c)R^(d), —C(═O)R^(a), —OC(═O)R^(a), —C(═O)OR^(b),        —OC(═O)OR^(b), —C(═O)NR^(c)R^(d), —OC(═O)NR^(c)R^(d),        —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a), —NR^(b)C(═O)OR^(b),        C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl,        C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₂-C₆alkenyl, or        C₂-C₆alkynyl;    -   or R³ and R⁴ are taken together to form an optionally        substituted ring;    -   L is a bond or —C(═O)—;    -   Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;        each optionally substituted with one or more R^(A);    -   each R^(A) is independently deuterium, halogen, —CN, —OR^(b),        —SR^(b), —S(═O)R^(a), —S(═O)₂R^(a), —NO₂, —NR^(c)R^(d),        —NHS(═O)₂R^(a), —S(═O)₂NR^(c)R^(d), —C(═O)R^(a), —OC(═O)R^(a),        —C(═O)OR^(b), —OC(═O)OR^(b), —C(═O)NR^(c)R^(d),        —OC(═O)NR^(c)R^(d), —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a),        —NR^(b)C(═O)OR^(b), C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,        C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl,        or heteroaryl; wherein each alkyl, alkenyl, alkenyl, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl is independently        optionally substituted with one or more oxo, deuterium, halogen,        —CN, —OR^(b), —NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b),        —C(═O)NR^(c)R^(d), C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   or two R^(A) on the same carbon are taken together to form an        oxo;    -   X is —CR^(x)— or —N—;    -   R^(x) is hydrogen, deuterium, halogen, —CN, —OR^(b), —SR^(b),        —S(═O)R^(a), —S(═O)₂R^(a), —NO₂, —NR^(c)R^(d), —NHS(═O)₂R^(a),        —S(═O)₂NR^(c)R^(d), —C(═O)R^(a), —OC(═O)R^(a), —C(═O)OR^(b),        —OC(═O)OR^(b), —C(═O)NR^(c)R^(d), —OC(═O)NR^(c)R^(d),        —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a), —NR^(b)C(═O)OR^(b),        C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl,        C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₂-C₆alkenyl, or        C₂-C₆alkynyl;    -   R⁵ is halogen, —CN, —OR⁸, —SR⁸, —S(═O)R⁷, —S(═O)₂R⁷, —NO₂,        —NR⁹R¹⁰, —NHS(═O)₂R⁷, —S(═O)₂NR⁹R¹⁰, —C(═O)R⁷, —OC(═O)R⁷,        —C(═O)OR⁸, —OC(═O)OR⁸, —C(═O)NR⁹R¹⁰, —OC(═O)NR⁹R¹⁰,        —NR⁸C(═O)NR⁹R¹⁰, —NR⁸C(═O)R⁷, —NR⁸C(═O)OR⁸, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,        C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl,        alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one or        more oxo, deuterium, halogen, —CN, —OR^(b), —NR^(c)R^(d),        —C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆alkyl, or        C₁-C₆haloalkyl;    -   or R^(x) and R⁵ are taken together to form ring D optionally        substituted with one or more R^(D);    -   Ring D is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;    -   each R^(D) is independently hydrogen, deuterium, halogen, —CN,        —OR^(b), —SR^(b), —S(═O)R^(a), —S(═O)₂R^(a), —NO₂, —NR^(c)R^(d),        —NHS(═O)₂R^(a), —S(═O)₂NR^(c)R^(d), —C(═O)R^(a), —OC(═O)R^(a),        —C(═O)OR^(b), —OC(═O)OR^(b), —C(═O)NR^(c)R^(d),        —OC(═O)NR^(c)R^(d), —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a),        —NR^(b)C(═O)OR^(b), C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,        C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl,        or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl is independently        optionally substituted with one or more oxo, deuterium, halogen,        —CN, —OR^(b), —NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b),        —C(═O)NR^(c)R^(d), C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   or two R^(D) on the same carbon are taken together to form an        oxo;    -   R⁷ is C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl,        C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,        cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each        alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one or        more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH₂, —C(═O)Me,        —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   each R⁸ is independently hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,        C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl,        or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl is independently        optionally substituted with one or more oxo, deuterium, halogen,        —CN, —OH, —OMe, —NH₂, —C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl,        or C₁-C₆haloalkyl;    -   R⁹ and R¹⁰ are independently hydrogen, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,        C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl,        alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one or        more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH₂, —C(═O)Me,        —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   or R⁹ and R¹⁰ are taken together with the nitrogen atom to which        they are attached to form a heterocycloalkyl optionally        substituted with one or more oxo, deuterium, halogen, —CN, —OH,        —OMe, —NH₂, —C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or        C₁-C₆haloalkyl;    -   each R^(a) is independently C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,        C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl,        or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl is independently        optionally substituted with one or more oxo, deuterium, halogen,        —CN, —OH, —OMe, —NH₂, —C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl,        or C₁-C₆haloalkyl;    -   each R^(b) is independently hydrogen, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,        C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl,        alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one or        more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH₂, —C(═O)Me,        —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   each R^(c) and R^(d) is independently hydrogen, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,        C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl,        alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one or        more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH₂, —C(═O)Me,        —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   or R^(c) and R^(d) are taken together with the nitrogen atom to        which they are attached to form a heterocycloalkyl optionally        substituted with one or more oxo, deuterium, halogen, —CN, —OH,        —OMe, —NH₂, —C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or        C₁-C₆haloalkyl.

In some embodiments of a compound of Formula (II) or (II′), L is a bond.In some embodiments of a compound of Formula (II) or (II′), L is—C(═O)—.

In some embodiments of a compound of Formula (II) or (II′), Ring A isheterocycloalkyl or heteroaryl; each optionally substituted with one ormore R^(A). In some embodiments of a compound of Formula (II) or (II′),Ring A is a 5-membered heterocycloalkyl or a 5-membered heteroaryl; eachoptionally substituted with one or more R^(A). In some embodiments of acompound of Formula (II) or (II′), Ring A is heteroaryl optionallysubstituted with one or more R^(A).

In some embodiments of a compound of Formula (II) or (II′), each R^(A)is independently deuterium, halogen, —CN, —OR^(b), —NR^(c)R^(d),—C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d), —OC(═O)NR^(c)R^(d),C₁-C₆alkyl, C₁-C₆haloalkyl, or C₁-C₆deuteroalkyl. In some embodiments ofa compound of Formula (II) or (II′), each R^(A) is independentlydeuterium, halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, or C₁-C₆deuteroalkyl. Insome embodiments of a compound of Formula (II) or (II′), each R^(A) isindependently halogen or C₁-C₆alkyl. In some embodiments of a compoundof Formula (II) or (II′), each R^(A) is independently C₁-C₆alkyl.

In some embodiments of a compound of Formula (II) or (II′), R⁴ ishydrogen, deuterium, halogen, —CN, —OR^(b), —NR^(c)R^(d), —C(═O)R^(a),—C(═O)OR^(b), —C(═O)NR^(c)R^(d), —OC(═O)NR^(c)R^(d), C₁-C₆alkyl,C₁-C₆haloalkyl, or C₁-C₆deuteroalkyl. In some embodiments of a compoundof Formula (II) or (II′), R⁴ is hydrogen or —OR^(b). In some embodimentsof a compound of Formula (II) or (II′), R⁴ is —OR^(b). In someembodiments of a compound of Formula (II) or (II′), R⁴ is hydrogen.

In some embodiments of a compound of Formula (II) or (II′), X is —CH—.In some embodiments of a compound of Formula (II) or (II′), X is —N—.

In some embodiments of a compound of Formula (II) or (II′), the compoundis of Formula (IIa) or (II′a):

In some embodiments of a compound of Formula (II) or (II′), the compoundis of Formula (IIb) or (II′b):

In some embodiments of a compound of Formula (II), (II′), (IIa), (II′a),(IIb), or (II′b), R³ is hydrogen or C₁-C₆alkyl. In some embodiments of acompound of Formula (II), (II′), (IIa), (II′a), (IIb), or (II′b), R³ ishydrogen.

In some embodiments of a compound of Formula (II), (II′), (IIa), (II′a),(IIb), or (II′b), R¹ and R² are independently hydrogen, C₁-C₆alkyl,C₁-C₆haloalkyl, or C₁-C₆deuteroalkyl. In some embodiments of a compoundof Formula (II), (II′), (IIa), (II′a), (IIb), or (II′b), R¹ and R² areindependently hydrogen or C₁-C₆deuteroalkyl. In some embodiments of acompound of Formula (II), (II′), (IIa), (II′a), (IIb), or (II′b), R¹ ishydrogen. In some embodiments of a compound of Formula (II), (II′),(IIa), (II′a), (IIb), or (II′b), R² is C₁-C₆alkyl or C₁-C₆deuteroalkyl.In some embodiments of a compound of Formula (II), (II′), (IIa), (II′a),(IIb), or (II′b), R² is C₁-C₆deuteroalkyl.

In some embodiments of a compound of Formula (II), (II′), (IIa), (II′a),(IIb), or (II′b), R⁵ is halogen, —CN, —OR^(b), —NR⁹R¹⁰, —C(═O)R⁷,—C(═O)OR⁸, —C(═O)NR⁹R¹⁰, —NR⁸C(═O)NR⁹R¹⁰, —NR⁸C(═O)R⁷, —NR⁸C(═O)OR⁸,C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₂-C₆alkenyl,C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; whereineach alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl isindependently optionally substituted with one or more oxo, deuterium,halogen, —CN, —OR^(b), —NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b),—C(═O)NR^(c)R^(d), C₁-C₆alkyl, or C₁-C₆haloalkyl.

In some embodiments of a compound of Formula (II), (II′), (IIa), (II′a),(IIb), or (II′b), R⁵ is —OR⁸, —NR⁹R¹⁰, —C(═O)R⁷, —C(═O)OR⁸,—C(═O)NR⁹R¹⁰, —NR⁸C(═O)NR⁹R¹⁰, —NR⁸C(═O)R⁷, —NR⁸C(═O)OR⁸, cycloalkyl,heterocycloalkyl, aryl, or heteroaryl; wherein each cycloalkyl,heterocycloalkyl, and heteroaryl is independently optionally substitutedwith one or more oxo, deuterium, halogen, —CN, —OR^(b), —NR^(c)R^(d),—C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆alkyl, orC₁-C₆haloalkyl.

In some embodiments of a compound of Formula (II), (II′), (IIa), (II′a),(IIb), or (II′b), R⁵ is —OR⁸, —NR⁹R¹⁰, —NR⁸C(═O)R⁷, or aryl optionallysubstituted with one or more oxo, deuterium, halogen, —CN, —OR^(b),—NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆alkyl,or C₁-C₆haloalkyl.

In some embodiments of a compound of Formula (II), (II′), (IIa), (II′a),(IIb), or (II′b), R⁵ is —OR⁸, —NR⁹R¹⁰, —NR⁸C(═O)R⁷, cycloalkyl,heterocycloalkyl, aryl or heteroaryl; wherein each cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is independently optionallysubstituted with one or more oxo, deuterium, halogen, —CN, —OR^(b),NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆alkyl,or C₁-C₆haloalkyl. In some embodiments of a compound of Formula (II),(II′), (IIa), (II′a), (IIb), or (II′b), R⁵ is —NR⁸C(═O)R⁷. In someembodiments of a compound of Formula (II), (II′), (IIa), (II′a), (IIb),or (II′b), R⁵ is aryl optionally substituted with one or more oxo,deuterium, halogen, —CN, —OR^(b), —NR^(c)R^(d), —C(═O)R^(a),—C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆alkyl, or C₁-C₆haloalkyl.

In some embodiments of a compound of Formula (II), (II′), (IIa), (II′a),(IIb), or (II′b), R⁷ is C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl,cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl,cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independentlyoptionally substituted with one or more oxo, deuterium, halogen, —CN,—OH, —OMe, —C(═O)Me, —NH₂, —C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, orC₁-C₆haloalkyl. In some embodiments of a compound of Formula (II),(II′), (IIa), (II′a), (IIb), or (II′b), R⁷ is C₁-C₆alkyl,C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, or cycloalkyl; wherein each alkyl,cycloalkyl, and heterocycloalkyl is independently optionally substitutedwith one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH₂,—C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl. In someembodiments of a compound of Formula (II), (II′), (IIa), (II′a), (IIb),or (II′b), R⁷ is cycloalkyl optionally substituted with one or more oxo,deuterium, halogen, —CN, —OH, —OMe, —NH₂, —C(═O)Me, —C(═O)OH, —C(═O)OMe,C₁-C₆alkyl, or C₁-C₆haloalkyl. In some embodiments of a compound ofFormula (II), (II′), (IIa), (II′a), (IIb), or (II′b), R⁷ isunsubstituted cycloalkyl.

In some embodiments of a compound of Formula (II), (II′), (IIa), (II′a),(IIb), or (II′b), R⁸ is hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl,C₁-C₆deuteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroarylis independently optionally substituted with one or more oxo, deuterium,halogen, —CN, —OH, —OMe, —NH₂, —C(═O)Me, —C(═O)OH, —C(═O)OMe,C₁-C₆alkyl, or C₁-C₆haloalkyl. In some embodiments of a compound ofFormula (II), (II′), (IIa), (II′a), (IIb), or (II′b), R⁸ is hydrogen,C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, or cycloalkyl; whereineach alkyl, cycloalkyl, and heterocycloalkyl is independently optionallysubstituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe,—NH₂, —C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl.

In some embodiments of a compound of Formula (II), (II′), (IIa), (II′a),(IIb), or (II′b), R⁹ and R¹⁰ are independently hydrogen, C₁-C₆alkyl,C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, cycloalkyl, heterocycloalkyl, aryl,or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryland heteroaryl is independently optionally substituted with one or moreoxo, deuterium, halogen, —CN, —OH, —OMe, —NH₂, —C(═O)Me, —C(═O)OH,—C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl. In some embodiments of acompound of Formula (II), (II′), (IIa), (II′a), (IIb), or (II′b), R⁹ andR¹⁰ are independently hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl,C₁-C₆deuteroalkyl, or cycloalkyl; wherein each alkyl, cycloalkyl, andheterocycloalkyl is independently optionally substituted with one ormore oxo, deuterium, halogen, —CN, —OH, —OMe, —NH₂, —C(═O)Me, —C(═O)OH,—C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl.

In some embodiments of a compound of Formula (II), (II′), (IIa), (II′a),(IIb), or (II′b), R¹¹ is deuterium, halogen, —CN, —OR^(b), —NR^(c)R^(d),—C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆alkyl,C₁-C₆haloalkyl, or C₁-C₆deuteroalkyl. In some embodiments of a compoundof Formula (II), (II′), (IIa), (II′a), (IIb), or (II′b), R¹¹ isdeuterium, halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, or C₁-C₆deuteroalkyl. Insome embodiments of a compound of Formula (II), (II′), (IIa), (II′a),(IIb), or (II′b), R¹³ is halogen. In some embodiments of a compound ofFormula (II), (II′), (IIa), (II′a), (IIb), or (II′b), R¹¹ is hydrogen.

Also disclosed herein is a compound of Formula (III), or apharmaceutically acceptable salt, stereoisomer, or solvate thereof:

wherein:

-   -   Ring B is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;        provided that

is not

-   -   each R^(B) is independently hydrogen, deuterium, halogen, —CN,        —OR^(b), —SR^(b), —S(═O)R^(a), —S(═O)₂R^(a), —NO₂, —NR^(c)R^(d),        —NHS(═O)₂R^(a), —S(═O)₂NR^(c)R^(d), —C(═O)R^(a), —OC(═O)R^(a),        —(═O)OR^(b), —OC(═O)OR^(b), —C(═O)NR^(c)R^(d),        —OC(═O)NR^(c)R^(d), —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a),        —NR^(b)C(═O)OR^(b), C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,        C₂-C₆alkenyl, or C₂-C₆alkynyl;    -   or two R^(B) on the same carbon are taken together to form an        oxo;    -   or two R^(B) on adjacent atoms are taken together to form a        cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each        optionally substituted with one or more deuterium, oxo, halogen,        —CN, —OR^(b), —NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b),        —C(═O)NR^(c)R^(d), C₁-C₆alkyl, C₁-C₆deuteroalkyl, or        C₁-C₆haloalkyl;    -   n is 0-4;    -   each Y is independently C or N;    -   R³ is hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl, or        C₁-C₆deuteroalkyl;    -   R⁴ is hydrogen, deuterium, halogen, —CN, —OR^(b), —SR^(b),        —S(═O)R^(a), —S(═O)²R^(a), —NO₂, —NR^(c)R^(d), —NHS(═O)₂R^(a),        —S(═O)₂NR^(c)R^(d), —C(═O)R^(a), —OC(═O)R^(a), —C(═O)OR^(b),        —OC(═O)OR^(b), —C(═O)NR^(c)R^(d), —OC(═O)NR^(c)R^(d),        —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a), —NR^(b)C(═O)OR^(b),        C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl,        C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₂-C₆alkenyl, or        C₂-C₆alkynyl;    -   or R³ and R⁴ are taken together to form an optionally        substituted ring;    -   L is a bond or —C(═O)—;    -   Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;        each optionally substituted with one or more R^(A);    -   each R^(A) is independently deuterium, halogen, —CN, —OR^(b),        —SR^(b), —S(═O)R^(a), —S(═O)²R^(a), —NO₂, —NR^(c)R^(d),        —NHS(═O)₂R^(a), —S(═O)₂NR^(c)R^(d), —C(═O)R^(a), —OC(═O)R^(a),        —C(═O)OR^(b), —OC(═O)OR^(b), —C(═O)NR^(c)R^(d),        —OC(═O)NR^(c)R^(d), —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a),        —NR^(b)C(═O)OR^(b), C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₂-C₆alkenyl,        C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;        wherein each alkyl, alkenyl, alkynyl, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl is independently        optionally substituted with one or more oxo, deuterium, halogen,        —CN, —OR^(b), —NR^(c)R^(d), —C(═O)R^(a), —C(═O)NR^(c)R^(d),        C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   or two R^(A) on the same carbon are taken together to form an        oxo;    -   X is —CR^(x)— or —N—;    -   R^(x) is hydrogen, deuterium, halogen, —CN, —OR^(b), —SR^(b),        —S(═O)R^(a), —S(═O)₂R^(a), —NO₂, —NR^(c)R^(d), —NHS(═O)₂R^(a),        —S(═O)₂NR^(c)R^(d), —C(═O)R^(a), —OC(═O)R^(a), —C(═O)OR^(b),        —C(═O)OR^(b), —C(═O)NR^(c)R^(d), —OC(═O)NR^(c)R^(d),        —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a), —NR^(b)C(═O)OR^(b),        C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl,        C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₂-C₆alkenyl, or        C₂-C₆alkynyl;    -   R⁵ is halogen, —CN, —OR⁸, —SR⁸, —S(═O)R⁷, —S(═O)₂R⁷, —NO₂,        —NR⁹R¹⁰, —NHS(═O)₂R⁷, —S(═O)₂NR⁹R¹⁰, —C(═O)R⁷, —OC(═O)R⁷,        —C(═O)OR⁸, —OC(═O)OR⁸, —C(═O)NR⁹R¹⁰, —OC(═O)NR⁹R¹⁰,        —NR⁸C(═O)NR⁹R¹⁰, —NR⁸C(═O)R⁷, —NR⁸C(═O)OR⁸, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,        C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl,        alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one or        more oxo, deuterium, halogen, —CN, —OR^(b), —NR^(c)R^(d),        —C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆alkyl, or        C₁-C₆haloalkyl;    -   or R^(x) and R⁵ are taken together to form ring D optionally        substituted with one or more R^(D);    -   Ring D is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;    -   each R^(D) is independently hydrogen, deuterium, halogen, —CN,        —OR^(b), —SR^(b), —S(═O)R^(a), —S(═O)₂R^(a), —NO₂, —NR^(c)R^(d),        —NHS(═O)₂R^(a), —S(═O)₂NR^(c)R^(d), —C(═O)R^(a), —OC(═O)R^(a),        —C(═O)OR^(b), —OC(═O)OR^(b), —C(═O)NR^(c)R^(d),        —OC(═O)NR^(c)R^(d), —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a),        —NR^(b)C(═O)OR^(b), C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,        C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl,        or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl is independently        optionally substituted with one or more oxo, deuterium, halogen,        —CN, —OR^(b), —NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b),        —C(═O)NR^(c)R^(d), C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   or two R^(D) on the same carbon are taken together to form an        oxo;    -   R⁷ is C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl,        C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,        cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each        alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one or        more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH₂, —C(═O)Me,        —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   each R⁸ is independently hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,        C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl,        or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl is independently        optionally substituted with one or more oxo, deuterium, halogen,        —CN, —OH, —OMe, —NH₂, —C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl,        or C₁-C₆haloalkyl;    -   R⁹ and R¹⁰ are independently hydrogen, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,        C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl,        alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one or        more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH₂, —C(═O)Me,        —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   or R⁹ and R¹⁰ are taken together with the nitrogen atom to which        they are attached to form a heterocycloalkyl optionally        substituted with one or more oxo, deuterium, halogen, —CN, —OH,        —OMe, —NH₂, —C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or        C₁-C₆haloalkyl;    -   each R^(a) is independently C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,        C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl,        or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl is independently        optionally substituted with one or more oxo, deuterium, halogen,        —CN, —OH, —OMe, —NH₂, —C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl,        or C₁-C₆haloalkyl;    -   each R^(b) is independently hydrogen, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,        C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl,        alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one or        more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH₂, —C(═O)Me,        —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   each R^(c) and R^(d) is independently hydrogen, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,        C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl,        alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one or        more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH₂, —C(═O)Me,        —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   or R^(c) and R^(d) are taken together with the nitrogen atom to        which they are attached to form a heterocycloalkyl optionally        substituted with one or more oxo, deuterium, halogen, —CN, —OH,        —OMe, —NH₂, —C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or        C₁-C₆haloalkyl.

In some embodiments of a compound of Formula (III), L is a bond. In someembodiments of a compound of Formula (III), L is —C(═O)—.

In some embodiments of a compound of Formula (III), Ring A isheterocycloalkyl or heteroaryl; each optionally substituted with one ormore R^(A). In some embodiments of a compound of Formula (III), Ring Ais a 5-membered heterocycloalkyl or a 5-membered heteroaryl; eachoptionally substituted with one or more R^(A)A. In some embodiments of acompound of Formula (III), Ring A is heteroaryl optionally substitutedwith one or more R^(A).

In some embodiments of a compound of Formula (III), each R^(A) isindependently deuterium, halogen, —CN, —OR^(b), —NR^(c)R^(d),—C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d), —OC(═O)NR^(c)R^(d),C₁-C₆alkyl, C₁-C₆haloalkyl, or C₁-C₆deuteroalkyl. In some embodiments ofa compound of Formula (III), each R^(A) is independently deuterium,halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, or C₁-C₆deuteroalkyl. In someembodiments of a compound of Formula (III), each R^(A) is independentlyhalogen or C₁-C₆alkyl. In some embodiments of a compound of Formula(III), each R^(A) is independently C₁-C₆alkyl.

In some embodiments of a compound of Formula (III), R⁴ is hydrogen,deuterium, halogen, —CN, —OR^(b), —NR^(c)R^(d), —C(═O)R^(a),—C(═O)OR^(b), —C(═O)NR^(c)R^(d), —OC(═O)NR^(c)R^(d), C₁-C₆alkyl,C₁-C₆haloalkyl, or C₁-C₆deuteroalkyl. In some embodiments of a compoundof Formula (III), R⁴ is hydrogen or —OR^(b). In some embodiments of acompound of Formula (III), R⁴ is —OR^(b). In some embodiments of acompound of Formula (III), R⁴ is hydrogen.

In some embodiments of a compound of Formula (III), X is —CH—. In someembodiments of a compound of Formula (III) X is —N—.

In some embodiments of a compound of Formula (III), the compound is ofFormula (IIIa):

In some embodiments of a compound of Formula (III), the compound is ofFormula (IIIb):

In some embodiments of a compound of Formula (III), (IIIa), or (IIIb),R³ is hydrogen or C₁-C₆alkyl. In some embodiments of a compound ofFormula (III), (IIIa), or (IIIb), R³ is hydrogen.

In some embodiments of a compound of Formula (III), (IIIa), or (IIIb),R⁵ is halogen, —CN, —OR⁸, —NR⁹R¹⁰, —C(═O)R⁷, —C(═O)OR⁸, —C(═O)NR⁹R¹⁰,—NR⁸C(═O)NR⁹R¹⁰, —NR⁸C(═O)R⁷, —NR⁸C(═O)OR⁸, C₁-C₆alkyl, C₁-C₆haloalkyl,C₁-C₆deuteroalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl,heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is independently optionallysubstituted with one or more oxo, deuterium, halogen, —CN, —OR^(b),NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆alkyl,or C₁-C₆haloalkyl.

In some embodiments of a compound of Formula (III), (IIIa), or (IIIb),R⁵ is —OR⁸, —NR⁹R¹⁰, —C(═O)R⁷, —C(═O)OR⁸, —C(═O)NR⁹R¹⁰, NR⁸C(═O)NR⁹R¹⁰,—NR⁸C(═O)R⁷, —NR⁸C(═O)OR⁸, cycloalkyl, heterocycloalkyl, aryl, orheteroaryl; wherein each cycloalkyl, heterocycloalkyl, aryl, andheteroaryl is independently optionally substituted with one or more oxo,deuterium, halogen, —CN, —OR^(b), —NR^(c)R^(d), —C(═O)R^(a),—C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆alkyl, or C₁-C₆haloalkyl.

In some embodiments of a compound of Formula (III), (IIIa), or (IIIb),R⁵ is —OR⁸, —NR⁹R¹⁰, —NR⁸C(═O)R⁷, or aryl optionally substituted withone or more oxo, deuterium, halogen, —CN, —OR^(b), —NR^(c)R^(d),—C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆alkyl, orC₁-C₆haloalkyl.

In some embodiments of a compound of Formula (III), (IIIa), or (IIIb),is —OR⁸, —NR⁹R¹⁰, —NR⁸C(═O)R⁷, cycloalkyl, heterocycloalkyl, aryl, orheteroaryl; wherein each cycloalkyl, heterocycloalkyl, aryl, andheteroaryl is independently optionally substituted with one or more oxo,deuterium, halogen, —CN, —OR^(b), —NR^(c)R^(d), —C(═O)R^(a),—C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆alkyl, or C₁-C₆haloalkyl. In someembodiments of a compound of Formula (III), (IIIa), or (IIIb), R⁵ is—NR⁸C(═O)R⁷. In some embodiments of a compound of Formula (III), (IIIa),or (IIIb), R⁵ is aryl optionally substituted with one or more oxo,deuterium, halogen, —CN, —OR^(b), —NR^(c)R^(d), —C(═O)R^(a),—C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆alkyl, or C₁-C₆haloalkyl.

In some embodiments of a compound of Formula (III), (IIIa), or (IIIb),R⁷ is C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, cycloalkyl,heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is independently optionallysubstituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe,—NH₂, —C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl. Insome embodiments of a compound of Formula (III), (IIIa), or (IIIb), R⁷is C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, or cycloalkyl; whereineach alkyl, cycloalkyl, and heterocycloalkyl is independently optionallysubstituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe,—NH₂, —C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl. Insome embodiments of a compound of Formula (III), (IIIa), or (IIIb), R⁷is cycloalkyl optionally substituted with one or more oxo, deuterium,halogen, —CN, —OH, —OMe, —NH₂, —C(═O)Me, —C(═O)OH, —C(═O)OMe,C₁-C₆alkyl, or C₁-C₆haloalkyl. In some embodiments of a compound ofFormula (III), (IIIa), or (IIIb), R⁷ is unsubstituted cycloalkyl.

In some embodiments of a compound of Formula (III), (IIIa), or (IIIb),R⁸ is hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl,cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl,cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independentlyoptionally substituted with one or more oxo, deuterium, halogen, —CN,—OH, —OMe, —NH₂, —C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, orC₁-C₆haloalkyl. In some embodiments of a compound of Formula (III),(IIIa), or (IIIb), R⁸ is hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl,C₁-C₆deuteroalkyl, or cycloalkyl; wherein each alkyl, cycloalkyl, andheterocycloalkyl is independently optionally substituted with one ormore oxo, deuterium, halogen, —CN, —OH, —OMe, —NH₂, —C(═O)Me, —C(═O)OH,—C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl.

In some embodiments of a compound of Formula (III), (IIIa), or (IIIb),R⁹ and R¹⁰ are independently hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl,C₁-C₆deuteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroarylis independently optionally substituted with one or more oxo, deuterium,halogen, —CN, —OH, —OMe, —NH₂, —C(═O)Me, —C(═O)OH, —C(═O)OMe,C₁-C₆alkyl, or C₁-C₆haloalkyl. In some embodiments of a compound ofFormula (III), (IIIa), or (IIIb), R⁹ and R¹⁰ are independently hydrogen,C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, or cycloalkyl; whereineach alkyl, cycloalkyl, and heterocycloalkyl is independently optionallysubstituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe,—NH₂, —C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl.

In some embodiments of a compound of Formula (III), (IIIa), or (IIIb),Ring B is a heterocycloalkyl or heteroaryl.

In some embodiments of a compound of Formula (III), (IIIa), or (IIIb),

is

and n′ is 0-3.

In some embodiments of a compound of Formula (III), (IIIa), or (IIIb),each R^(B) is independently hydrogen, deuterium, halogen, —CN, —OR^(b),—NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆alkyl,C₁-C₆haloalkyl, or C₁-C₆deuteroalkyl; or two R^(B) on the same carbonare taken together to form an oxo. In some embodiments of a compound ofFormula (III), (IIIa), or (IIIb), each R^(B) is independently hydrogen,deuterium, halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, or C₁-C₆deuteroalkyl;two R^(B) on the same carbon are taken together to form an oxo.

In some embodiments of a compound of Formula (III), (IIIa), or (IIIb),two R^(B) on adjacent atoms are taken together to form a cycloalkyl,heterocycloalkyl, aryl, or heteroaryl; each optionally substituted withone or more deuterium, oxo, halogen, —CN, —OR^(b), —NR^(c)R^(d),—C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆alkyl,C₁-C₆deuteroalkyl, or C₁-C₆haloalkyl. In some embodiments of a compoundof Formula (III), (IIIa), or (IIIb), two R^(B) on adjacent atoms aretaken together to form a heterocycloalkyl or heteroaryl; each optionallysubstituted with one or more deuterium, oxo, halogen, —CN, —OR^(b),—NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆alkyl,C₁-C₆deuteroalkyl, or C₁-C₆haloalkyl.

In some embodiments of a compound of Formula (III), (IIIa), or (IIIb), nis 0. In some embodiments of a compound of Formula (III), (IIIa), or(IIIb), n is 1. In some embodiments of a compound of Formula (III),(IIIa), or (IIIb), n is 2. In some embodiments of a compound of Formula(III), (IIIa), (IIIb), n is 0-2. In some embodiments of a compound ofFormula (III), (IIIa), or (IIIb), n is 0 or 1. In some embodiments of acompound of Formula (III), (IIIa), or (IIIb), n is 1 or 2. In someembodiments of a compound of Formula (III), (IIIa), or (IIIb), n is 1-3.

In some embodiments of a compound of Formula (III), (IIIa), or (IIIb),n′ is 0. In some embodiments of a compound of Formula (III), (IIIa), or(IIIb), n′ is 1. In some embodiments of a compound of Formula (III),(IIIa), or (IIIb), n′ is 2. In some embodiments of a compound of Formula(III), (IIIa), or (IIIb), n′ is 0-2. In some embodiments of a compoundof Formula (III), (IIIa), or (IIIb), n′ is 0 or 1. In some embodimentsof a compound of Formula (III), (IIIa), or (IIIb), n′ is 1 or 2.

Also disclosed herein is a compound of Formula (IV), or apharmaceutically acceptable salt, stereoisomer, or solvate thereof:

wherein:

-   -   Ring C is a bicyclic ring system;    -   each R^(C) is independently hydrogen, oxo, deuterium, halogen,        —CN, —OR^(b), —SR^(b), —S(═O)R^(a), —S(═O)₂R^(a), —NO₂,        —NR^(c)R^(d), —NHS(═O)₂R^(a), —S(═O)₂NR^(c)R^(d), —C(═O)R^(a),        —OC(═O)R^(a), —C(═O)OR^(b), —OC(═O)OR^(b), —C(═O)NR^(c)R^(d),        —OC(═O)NR^(c)R^(d), —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a),        —NR^(b)C(═O)OR^(b), C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,        C₂-C₆alkenyl, or C₂-C₆alkynyl;    -   m is 0-4;    -   R¹² is —C(═O)NR¹R² or -L¹—R¹³;    -   R¹ and R² are independently hydrogen, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,        C₁-C₆aminoalkyl, C₂-C₆alkenyl, or C₂-C₆alkynyl;    -   L¹ is —O—, —NH—, or —N(CH₃)—;    -   R¹³ is C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl,        C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,        cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each        alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and        heteroaryl is independently optionally substituted with one or        more oxo, deuterium, halogen, —CN, —OR^(b), —NR^(c)R^(d),        —C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆alkyl, or        C₁-C₆haloalkyl;    -   L is a bond or —C(═O)—;    -   Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;        each optionally substituted with one or more R^(A);    -   each R^(A) is independently deuterium, halogen, —CN, —OR^(b),        —SR^(b), —S(═O)R^(a), —S(═O)₂R^(a), —NO₂, —NR^(c)R^(d),        —NHS(═O)₂R^(a), —S(═O)₂NR^(c)R^(d), —C(═O)R^(a), —OC(═O)R^(a),        —C(═O)OR^(b), —OC(═O)OR^(b), —C(═O)NR^(c)R^(d),        —OC(═O)NR^(c)R^(d), —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a),        —NR^(b)C(═O)OR^(b), C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,        C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl,        or heteroaryl; wherein each alkyl, alkenyl, alkenyl, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl is independently        optionally substituted with one or more oxo, deuterium, halogen,        —CN, —OR^(b), —NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b),        —C(═O)NR^(c)R^(d), C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   or two R^(A) on the same carbon are taken together to form an        oxo;    -   X is —CR^(x)— or —N—;    -   R^(x) is hydrogen, deuterium, halogen, —CN, —OR^(b), —SR^(b),        —S(═O)R^(a), —S(═O)₂R^(a), —NO₂, —NR^(c)R^(d), —NHS(═O)₂R^(a),        —S(═O)₂NR^(c)R^(d), —C(═O)R^(a), —OC(═O)R^(a), —C(═O)OR^(b),        —OC(═O)OR^(b), —C(═O)NR^(c)R^(d), —OC(═O)NR^(c)R^(d),        —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a), —NR^(b)C(═O)OR^(b),        C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl,        C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₂-C₆alkenyl, or        C₂-C₆alkynyl;    -   R⁵ is halogen, —CN, —OR⁸, —SR⁸, —S(═O)R⁷, —S(═O)₂R⁷, —NO₂,        —NR⁹R¹⁰, —NHS(═O)₂R⁷, —S(═O)₂NR⁹R¹⁰, —C(═O)R⁷, —OC(═O)R⁷,        —C(═O)OR⁸, —OC(═O)OR⁸, —C(═O)NR⁹R¹⁰, —OC(═O)NR⁹R¹⁰,        —NR⁸C(═O)NR⁹R¹⁰, —NR⁸C(═O)R⁷, —NR⁸C(═O)OR⁸, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,        C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl,        alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one or        more oxo, deuterium, halogen, —CN, —OR^(b), —NR^(c)R^(d),        —C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆alkyl, or        C₁-C₆haloalkyl;    -   or R^(x) and R⁵ are taken together to form ring D optionally        substituted with one or more R^(D);    -   Ring D is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;    -   each R^(D) is independently hydrogen, deuterium, halogen, —CN,        —OR^(b), —SR^(b), —S(═O)R^(a), —S(═O)₂R^(a), —NO₂, —NR^(c)R^(d),        —NHS(═O)₂R^(a), —S(═O)₂NR^(c)R^(d), —C(═O)R^(a), —OC(═O)R^(a),        —C(═O)OR^(b), —OC(═O)OR^(b), —C(═O)NR^(c)R^(d),        —OC(═O)NR^(c)R^(d), —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a),        —NR^(b)C(═O)OR^(b), C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,        C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl,        or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl is independently        optionally substituted with one or more oxo, deuterium, halogen,        —CN, —OR^(b), —NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b),        —C(═O)NR^(c)R^(d), C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   or two R^(D) on the same carbon are taken together to form an        oxo;    -   R⁷ is C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl,        C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,        cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each        alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one or        more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH₂, —C(═O)Me,        —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   each R⁸ is independently hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,        C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl,        or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl is independently        optionally substituted with one or more oxo, deuterium, halogen,        —CN, —OH, —OMe, —NH₂, —C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl,        or C₁-C₆haloalkyl;    -   R⁹ and R¹⁰ are independently hydrogen, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,        C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl,        alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one or        more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH₂, —C(═O)Me,        —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   or R⁹ and R¹⁰ are taken together with the nitrogen atom to which        they are attached to form a heterocycloalkyl optionally        substituted with one or more oxo, deuterium, halogen, —CN, —OH,        —OMe, —NH₂, —C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or        C₁-C₆haloalkyl;    -   each R^(a) is independently C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,        C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl,        or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl is independently        optionally substituted with one or more oxo, deuterium, halogen,        —CN, —OH, —OMe, —NH₂, —C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl,        or C₁-C₆haloalkyl;    -   each R^(b) is independently hydrogen, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,        C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl,        alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one or        more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH₂, —C(═O)Me,        —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   each R^(c) and R^(d) is independently hydrogen, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,        C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl,        alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one or        more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH₂, —C(═O)Me,        —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   or R^(c) and R^(d) are taken together with the nitrogen atom to        which they are attached to form a heterocycloalkyl optionally        substituted with one or more oxo, deuterium, halogen, —CN, —OH,        —OMe, —NH₂, —C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or        C₁-C₆haloalkyl.

In some embodiments of a compound of Formula (IV), L is a bond. In someembodiments of a compound of Formula (IV), L is —C(═O)—.

In some embodiments of a compound of Formula (IV), Ring A isheterocycloalkyl or heteroaryl; each optionally substituted with one ormore R^(A). In some embodiments of a compound of Formula (IV), Ring A isa 5-membered heterocycloalkyl or a 5-membered heteroaryl; eachoptionally substituted with one or more R^(A). In some embodiments of acompound of Formula (IV), Ring A is heteroaryl optionally substitutedwith one or more R^(A).

In some embodiments of a compound of Formula (IV), each R^(A) isindependently deuterium, halogen, —CN, —OR^(b), —NR^(c)R^(d),—C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d), —OC(═O)NR^(c)R^(d),C₁-C₆alkyl, C₁-C₆haloalkyl, or C₁-C₆deuteroalkyl. In some embodiments ofa compound of Formula (IV), each R^(A) is independently deuterium,halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, or C₁-C₆deuteroalkyl. In someembodiments of a compound of Formula (IV), each R^(A) is independentlyhalogen or C₁-C₆alkyl. In some embodiments of a compound of Formula(IV), each R^(A) is independently C₁-C₆alkyl.

In some embodiments of a compound of Formula (IV), R⁴ is hydrogen,deuterium, halogen, —CN, —OR^(b), —NR^(c)R^(d), —C(═O)R^(a),—C(═O)OR^(b), —C(═O)NR^(c)R^(d), —OC(═O)NR^(c)R^(d), C₁-C₆alkyl,C₁-C₆haloalkyl, or C₁-C₆deuteroalkyl. In some embodiments of a compoundof Formula (IV), R⁴ is hydrogen or —OR^(b). In some embodiments of acompound of Formula (IV), R⁴ is —OR^(b). In some embodiments of acompound of Formula (IV), R⁴ is hydrogen.

In some embodiments of a compound of Formula (IV), X is —CH—. In someembodiments of a compound of Formula (IV), X is —N—.

In some embodiments of a compound of Formula (IV), the compound is ofFormula (IVa):

In some embodiments of a compound of Formula (IV), the compound is ofFormula (IVb):

In some embodiments of a compound of Formula (IV), (IVa), or (IVb), R¹²is —C(═O)NR¹R².

In some embodiments of a compound of Formula (IV), (IVa), or (IVb), R¹and R² are independently hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl, orC₁-C₆deuteroalkyl. In some embodiments of a compound of Formula (IV),(IVa), or (IVb), R¹ and R² are independently hydrogen orC₁-C₆deuteroalkyl. In some embodiments of a compound of Formula (IV),(IVa), or (IVb), R¹ is hydrogen. In some embodiments of a compound ofFormula (IV), (IVa), or (IVb), R² is C₁-C₆alkyl or C₁-C₆deuteroalkyl. Insome embodiments of a compound of Formula (IV), (IVa), or (IVb), R² isC₁-C₆deuteroalkyl.

In some embodiments of a compound of Formula (IV), (IVa), or (IVb), R¹²is -L¹—R¹³.

In some embodiments of a compound of Formula (IV), (IVa), or (IVb), L¹is —NH—. In some embodiments of a compound of Formula (IV), (IVa), or(IVb), L¹ is —O— or —NH—.

In some embodiments of a compound of Formula (IV), (IVa), or (IVb), R¹³is C₁-C₆alkyl, C₁-C₆haloalkyl, or C₁-C₆deuteroalkyl.

In some embodiments of a compound of Formula (IV), (IVa), or (IVb), R⁵is halogen, —CN, —OR⁸, —NR⁹R¹⁰, —C(═O)R⁷, —C(═O)OR⁸, —C(═O)NR⁹R¹⁰,—NR⁸C(═O)NR⁹R¹⁰, —NR⁸C(═O)R⁷, —NR⁸C(═O)OR⁸, C₁-C₆alkyl, C₁-C₆haloalkyl,C₁-C₆deuteroalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl,heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is independently optionallysubstituted with one or more oxo, deuterium, halogen, —CN, —OR^(b),—NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆alkyl,or C₁-C₆haloalkyl.

In some embodiments of a compound of Formula (IV), (IVa), or (IVb), R⁵is —OR⁸, —NR⁹R¹⁰, —C(═O)R⁷, —C(═O)OR⁸, —C(═O)NR⁹R¹⁰, —NR⁸C(═O)NR⁹R¹⁰,—NR⁸C(═O)R⁷, —NR⁸C(═O)OR⁸, cycloalkyl, heterocycloalkyl, aryl, orheteroaryl; wherein each cycloalkyl, heterocycloalkyl, aryl, andheteroaryl is independently optionally substituted with one or more oxo,deuterium, halogen, —CN, —OR^(b), —NR^(c)R^(d), —C(═O)R^(a),—C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆alkyl, or C₁-C₆haloalkyl.

In some embodiments of a compound of Formula (IV), (IVa), or (IVb), R⁵is —OR⁸, —NR⁹R¹⁰, —NR⁸C(═O)R⁷,l or aryl optionally substituted with oneor more oxo, deuterium, halogen, —CN, —OR^(b), —NR^(c)R^(d),—C(═O)R^(a), —C(═O)OR⁸, —C(═O)NR^(c)R^(d), C₁-C₆alkyl, orC₁-C₆haloalkyl.

In some embodiments of a compound of Formula (IV), (IVa), or (IVb), R⁵is —OR⁸, —NR⁹R¹⁰, —NR⁸C(═O)R⁷, cycloalkyl, heterocycloalkyl, aryl, orheteroaryl; wherein each cycloalkyl, heterocycloalkyl, aryl, andheteroaryl is independently optionally substituted with one or more oxo,deuterium, halogen, —CN, —OR^(b), —NR^(c)R^(d), —C(═O)R^(a),—C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆alkyl, or C₁-C₆haloalkyl. In someembodiments of a compound of Formula (IV), (IVa), or (IVb), R⁵ is—NR⁸C(═O)R⁷. In some embodiments of a compound of Formula (IV), (IVa),or (IVb), R⁵ is aryl optionally substituted with one or more oxo,deuterium, halogen, —CN, —OR^(b), —NR^(c)R^(d), —C(═O)R^(a),—C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆alkyl, or C₁-C₆haloalkyl.

In some embodiments of a compound of Formula (IV), (IVa), or (IVb), R⁷is C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, cycloalkyl,heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is independently optionallysubstituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe,—NH₂, —C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl. Insome embodiments of a compound of Formula (IV), (IVa), or (IVb), R⁷ isC₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, or cycloalkyl; whereineach alkyl, cycloalkyl, and heterocycloalkyl is independently optionallysubstituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe,—NH₂, —C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl. Insome embodiments of a compound of Formula (IV), (IVa), or (IVb), R⁷ iscycloalkyl optionally substituted with one or more oxo, deuterium,halogen, —CN, —OH, —OMe, —NH₂, —C(═O)Me, —C(═O)OH, —C(═O)OMe,C₁-C₆alkyl, or C₁-C₆haloalkyl. In some embodiments of a compound ofFormula (IV), (IVa), or (IVb), R⁷ is unsubstituted cycloalkyl.

In some embodiments of a compound of Formula (IV), (IVa), or (IVb), R⁸is hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, cycloalkyl,heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is independently optionallysubstituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe,—C(═O)Me, —C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl. In some embodimentsof a compound of Formula (IV), (IVa), or (IVb), R⁸ is hydrogen,C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, or cycloalkyl; whereineach alkyl, cycloalkyl, and heterocycloalkyl is independently optionallysubstituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe,—NH₂, —C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl.

In some embodiments of a compound of Formula (IV), (IVa), or (IVb), R⁹and R¹⁰ are independently hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl,C₁-C₆deuteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroarylis independently optionally substituted with one or more oxo, deuterium,halogen, —CN, —OH, —OMe, —C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, orC₁-C₆haloalkyl. In some embodiments of a compound of Formula (IV),(IVa), or (IVb), R⁹ and R¹⁰ are independently hydrogen, C₁-C₆alkyl,C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, or cycloalkyl; wherein each alkyl,cycloalkyl, and heterocycloalkyl is independently optionally substitutedwith one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH₂,—C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl.

In some embodiments of a compound of Formula (IV), (IVa), or (IVb), RingC is indole or benzimidazole.

In some embodiments of a. compound of Formula (IV), (IVa), or (IVb),each R^(C) is independently deuterium, halogen, —CN, —OR^(b),—NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d),—OC(═O)NR^(c)R^(d), C₁-C₆alkyl, C₁-C₆haloalkyl, or C₁-C₆deuteroalkyl.

In some embodiments of a compound of Formula (IV), (IVa), or (IVb), eachR^(C) is independently deuterium, halogen, C₁-C₆alkyl, C₁-C₆haloalkyl,or C₁-C₆deuteroalkyl. In some embodiments of a compound of Formula (IV),(IVa), or (IVb), each R^(C) is independently halogen or C₁-C₆alkyl.

In some embodiments of a compound of Formula (IV), (IVa), or (IVb), m is0. In some embodiments of a compound of Formula (IV), (IVa), or (IVb), mis 1. In some embodiments of a compound of Formula (IV), (IVa), or(IVb), m is 2. In some embodiments of a compound of Formula (IV), (IVa),or (IVb), m is 0 or 1. In some embodiments of a compound of Formula(IV), (IVa), or (IVb), m is 0-2. In some embodiments of a compound ofFormula (IV), (IVa), or (IVb), m is 1 or 2. In some embodiments of acompound of Formula (IV), (IVa), or (IVb), m is 1-3.

Also disclosed herein is a compound of Formula (V), or apharmaceutically acceptable salt, stereoisomer, or solvate thereof:

wherein:

-   -   Ring D is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;    -   each R^(D) is independently hydrogen, deuterium, halogen, —CN,        —OR^(b), —SR^(b), —S(═O)R^(a), —S(═O)₂R^(a), —NO₂, —NR^(c)R^(d),        —NHS(═O)₂R^(a), —S(═O)₂NR^(c)R^(d), —C(═O)R^(a), —OC(═O)R^(a),        —C(═O)OR^(b), —OC(═O)OR^(b), —C(═O)NR^(c)R^(d),        —OC(═O)NR^(c)R^(d), —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a),        —NR^(b)C(═O)OR^(b), C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,        C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl,        or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl is independently        optionally substituted with one or more oxo, deuterium, halogen,        —CN, —OR^(b), —NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b),        —C(═O)NR^(c)R^(d), C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   or two R^(D) on the same carbon are taken together to form an        oxo;    -   or two R^(D) on adjacent atoms are taken together to form a        cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each        optionally substituted with one or more deuterium, oxo, halogen,        —CN, —OR^(b), —NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b),        —C(═O)NR^(c)R^(d), C₁-C₆alkyl, C₁-C₆deuteroalkyl, or        C₁-C₆haloalkyl;    -   r is 0-4;    -   each Y is independently C or N;    -   R¹ and R² are independently hydrogen, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,        C₁-C₆aminoalkyl, C₂-C₆alkenyl, or C₂-C₆alkynyl;    -   R³ is hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl, or        C₁-C₆deuteroalkyl;    -   R⁴ is hydrogen, deuterium, halogen, —CN, —OR^(b), —SR^(b),        —S(═O)R^(a), —S(═O)₂R^(a), —NO₂, —NR^(c)R^(d), —NHS(═O)₂R^(a),        —S(═O)₂NR^(c)R^(d), —C(═O)R^(a), —OC(═O)R^(a), —C(═O)OR^(b),        —OC(═O)OR^(b), —C(═O)NR^(c)R^(d), —OC(═O)NR^(c)R^(d),        —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a), —NR^(b)C(═O)OR^(b),        C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl,        C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₂-C₆alkenyl, or        C₂-C₆alkynyl;    -   or R³ and R⁴ are taken together to form an optionally        substituted ring;    -   L is a bond or —C(═O)—;    -   Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;        each optionally substituted with one or more R^(A);    -   each R^(A) is independently deuterium, halogen, —CN, —OR^(b),        —SR^(b), —S(═O)R^(a), —S(═O)₂R^(a), —NO₂, —NR^(c)R^(d),        —NHS(═O)₂R^(a), —S(═O)₂NR^(c)R^(d), —C(═O)R^(a), —OC(═O)R^(a),        —C(═O)OR^(b), —OC(═O)OR^(b), —C(═O)NR^(c)R^(d),        —OC(═O)NR^(c)R^(d), —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a),        —NR^(b)C(═O)OR^(b), C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,        C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl,        or heteroaryl; wherein each alkyl, alkenyl, alkenyl, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl is independently        optionally substituted with one or more oxo, deuterium, halogen,        —CN, —OR^(b), —NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b),        —C(═O)NR^(c)R^(d), C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   or two R^(A) on the same carbon are taken together to form an        oxo;    -   X is —CR^(x)— or —N—;    -   each R^(x) is independently hydrogen, deuterium, halogen, —CN,        —OR^(b), —SR^(b), —S(═O)R^(a), —S(═O)₂R^(a), —NO₂, —NR^(c)R^(d),        —NHS(═O)₂R^(a), —S(═O)₂NR^(c)R^(d), —C(═O)R^(a), —OC(═O)R^(a),        —C(═O)OR^(b), —OC(═O)OR^(b), —C(═O)NR^(c)R^(d),        —OC(═O)NR^(c)R^(d), —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a),        —NR^(b)(═O)OR^(b), C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,        C₂-C₆alkenyl, or C₂-C₆alkynyl;    -   each R^(a) is independently C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,        C₂-C₆alkenyl, C₁-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl,        or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl is independently        optionally substituted with one or more oxo, deuterium, halogen,        —CN, —OH, OMe, —NH₂, —C(═O)Me, —C(═OOH, —C(═O)OMe, C₁-C₆alkyl,        or C₁-C₆haloalkyl;    -   each R^(b) is independently hydrogen, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,        C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl,        alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one or        more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH₂, —C(═O)Me,        —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   each R^(c) and R^(d) is independently hydrogen, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,        C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl,        alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one or        more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH₂, —C(═O)Me,        —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   or R^(c) and R^(d) are taken together with the nitrogen atom to        which they are attached to form a heterocycloalkyl optionally        substituted with one or more oxo, deuterium, halogen, —CN, —OH,        —OMe, —NH₂, —C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or        C₁-C₆haloalkyl.

In some embodiments of a compound of Formula (V), L is a bond. In someembodiments of a compound of Formula (V), L is —C(═O)—.

In some embodiments of a compound of Formula (V), Ring A isheterocycloalkyl or heteroaryl; each optionally substituted with one ormore R^(A). In some embodiments of a compound of Formula (V), Ring A isa 5-membered heterocycloalkyl or a 5-membered heteroaryl; eachoptionally substituted with one or more R^(A). In some embodiments of acompound of Formula (V), Ring A is heteroaryl optionally substitutedwith one or more R^(A).

In some embodiments of a compound of Formula (V), each R^(A) isindependently deuterium, halogen, —CN, —OR^(b), —NR^(c)R^(d),—C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d), —OC(═O)NR^(c)R^(d),C₁-C₆alkyl, C₁-C₆haloalkyl, or C₁-C₆deuteroalkyl. In some embodiments ofa compound of Formula (V), each R^(A) is independently deuterium,halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, or C₁-C₆deuteroalkyl. In someembodiments of a compound of Formula (V), each R^(A) is independentlyhalogen or C₁-C₆alkyl. In some embodiments of a compound of Formula (V),each R^(A) is independently C₁-C₆alkyl.

In some embodiments of a compound of Formula (V), R⁴ is hydrogen,deuterium, halogen, —CN, —OR^(b), —NR^(c)R^(d), —C(═O)R^(a),—C(═O)OR^(b), —C(═O)NR^(c)R^(d), —OC(═O)NR^(c)R^(d), C₁-C₆alkyl,C₁-C₆haloalkyl, C₁-C₆deuteroalkyl. In some embodiments of a compound ofFormula (V), R⁴ is hydrogen or —OR^(b). In some embodiments of acompound of Formula (V), R⁴ is —OR^(b). In some embodiments of acompound of Formula (V), R⁴ is hydrogen.

In some embodiments of a compound of Formula (V), each X is —N—. In someembodiments of a compound of Formula (V), each X is —CH—. In someembodiments of a compound of Formula (V), one X is —N— and the other is—CH—.

In some embodiments of a compound of Formula (V), the compound is ofFormula (Va):

In some embodiments of a compound of Formula (V), the compound is ofFormula (Vb):

In some embodiments of a compound of Formula (V), (Va), or (Vb), R³ ishydrogen or C₁-C₆alkyl. In some embodiments of a compound of Formula(V), (Va), or (Vb), R³ is hydrogen.

In some embodiments of a compound of Formula (V), (Va), or (Vb), R¹ andR² are independently hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl, orC₁-C₆deuteroalkyl. In some embodiments of a compound of Formula (V),(Va), or (Vb), R¹ and R² are independently hydrogen orC₁-C₆deuteroalkyl. In some embodiments of a compound of Formula (V),(Va), or (Vb), R¹ is hydrogen. In some embodiments of a compound ofFormula (V), (Va), or (Vb), R² is C₁-C₆alkyl or C₁-C₆deuteroalkyl. Insome embodiments of a compound of Formula (V), (Va), or (Vb), R² isC₁-C₆deuteroalkyl.

In some embodiments of a compound of Formula (V), (Va), or (Vb), Ring Dis a heterocycloalkyl or heteroaryl.

In some embodiments of a compound of Formula (V), (Va), or (Vb),

is

and r′ is 0-3.

In some embodiments of a compound of Formula (V), (Va), or (Vb), eachR^(D) is independently hydrogen, deuterium, halogen, —CN, —OR^(b),—C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆alkyl,C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, cycloalkyl, or heterocycloalkyl. Insome embodiments of a compound of Formula (V), (Va), or (Vb), each R^(D)is independently hydrogen, deuterium, halogen, C₁-C₆alkyl,C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, or cycloalkyl. In some embodiments ofa compound of Formula (V), (Va), or (Vb), each R^(D) is independentlyhydrogen or cycloalkyl.

In some embodiments of a compound of Formula (V), (Va), or (Vb), r is 0.In some embodiments of a compound of Formula (V), (Va), or (Vb), r is 1.In some embodiments of a compound of Formula (V), (Va), or (Vb), r is 2.In some embodiments of a compound of Formula (V), (Va), or (Vb), r is0-2. In some embodiments of a compound of Formula (V), (Va), or (Vb), ris 0 or 1. In some embodiments of a compound of Formula (V), (Va), or(Vb), r is 1 or 2. In some embodiments of a compound of Formula (V),(Va), or (Vb), r is 1-3.

In some embodiments of a compound of Formula (V), (Va), or (Vb), r′ is0. In some embodiments of a compound of Formula (V), (Va), or (Vb), r′is 1. In some embodiments of a compound of Formula (V), (Va), or (Vb),r′ is 2. In some embodiments of a compound of Formula (V), (Va), or(Vb), r′ is 0-2. In some embodiments of a compound of Formula (V), (Va),or (Vb), r′ is 0 or 1. In some embodiments of a compound of Formula (V),(Va), or (Vb), r′ is 1 or 2. In some embodiments of a compound ofFormula (V), (Va), or (Vb), r′ is 1-3.

Also disclosed herein is a compound of Formula (VI), or apharmaceutically acceptable salt, stereoisomer, or solvate thereof:

wherein:

-   -   Ring E is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl,        each optionally substituted with one or more R^(E);    -   each R^(E) is independently deuterium, halogen, —CN, —OR^(b),        —SR^(b), —S(═O)R^(a), —S(═O)₂R^(a), —NO₂, —NR^(c)R^(d),        —NHS(═O)₂R^(a), —S(═O)₂NR^(c)R^(d), —C(═O)R^(a), —OC(═O)R^(a),        —C(═O)OR^(b), —OC(═O)OR^(b), —C(═O)NR^(c)R^(d),        —OC(═O)NR^(c)R^(d), —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a),        —NR^(b)C(═O)OR^(b), C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,        C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl,        or heteroaryl; wherein each alkyl, alkenyl, alkenyl, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl is independently        optionally substituted with one or more oxo, deuterium, halogen,        —CN, —OR^(b), —NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b),        —C(═O)NR^(c)R^(d), C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   or two R^(E) on the same carbon are taken together to form an        oxo;    -   L² is a bond, —O—, or        ;    -   R¹ and R² are independently hydrogen, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,        C₁-C₆aminoalkyl, C₂-C₆alkenyl, or C₂-C₆alkynyl;    -   R³ is hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl, or        C₁-C₆deuteroalkyl;    -   R⁴ is hydrogen, deuterium, halogen, —CN, —OR^(b), —SR^(b),        —S(═O)R^(a), —S(═O)₂R^(a), —NO₂, —NR^(c)R^(d), —NHS(═O)₂R^(a),        —S(═O)₂NR^(c)R^(d), —C(═O)R^(a), —OC(═O)R^(a), —C(═O)OR^(b),        —OC(═O)OR^(b), —C(═O)NR^(c)R^(d), —OC(═O)NR^(c)R^(d),        —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a), —NR^(b)C(═O)OR^(b),        C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl,        C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₂-C₆alkenyl, or        C₂-C₆alkynyl;    -   or R³ and R⁴ are taken together to form an optionally        substituted ring;    -   L is a bond or —C(═O)—;    -   Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;        each optionally substituted with one or more R^(A);    -   each R^(A) is independently deuterium, halogen, —CN, —OR^(b),        —SR^(b), —S(═O)R^(a), —S(═O)₂R^(a), —NO₂, —NR^(c)R^(d),        —NHS(═O)₂R^(a), —S(═O)₂NR^(c)R^(d), —C(═O)R^(a), —OC(═O)R^(a),        —C(═O)OR^(b), —OC(═O)OR^(b), —C(═O)NR^(c)R^(d),        —OC(═O)NR^(c)R^(d), —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a),        —NR^(b)C(═O)OR^(b), C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,        C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl,        or heteroaryl; wherein each alkyl, alkenyl, alkenyl, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl is independently        optionally substituted with one or more oxo, deuterium, halogen,        —CN, —OR^(b), —NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b),        —C(═O)NR^(c)R^(d), C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   or two R^(A) on the same carbon are taken together to form an        oxo;    -   X is —CR^(x)— or —N—;    -   R^(x) is hydrogen, deuterium, halogen, —CN, —OR^(b), —SR^(b),        —S(═O)R^(a), —S(═O)₂R^(a), —NO₂, —NR^(c)R^(d), —NHS(═O)₂R^(a),        —S(═O)₂NR^(c)R^(d), —C(═O)R^(a), —OC(═O)R^(a), —C(═O)OR^(b),        —OC(═O)OR^(b), —C(═O)NR^(c)R^(d), —OC(═O)NR^(c)R^(d),        —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a), —NR^(b)C(═O)OR^(b),        C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl,        C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₂-C₆alkenyl, or        C₂-C₆alkynyl;    -   each R^(a) is independently C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,        C₂-C₆alkenyl, C₁-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl,        or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl is independently        optionally substituted with one or more oxo, deuterium, halogen,        —CN, —OH, OMe, —NH₂, —C(═O)Me, —C(═OOH, —C(═O)OMe, C₁-C₆alkyl,        or C₁-C₆haloalkyl;    -   each R^(b) is independently hydrogen, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,        C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl,        alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one or        more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH₂, —C(═O)Me,        —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   each R^(c) and R^(d) is independently hydrogen, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,        C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl,        alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one or        more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH₂, —C(═O)Me,        —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   or R^(c) and R^(d) are taken together with the nitrogen atom to        which they are attached to form a heterocycloalkyl optionally        substituted with one or more oxo, deuterium, halogen, —CN, —OH,        —OMe, —NH₂, —C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or        C₁-C₆haloalkyl.

In some embodiments of a compound of Formula (VI), L is a bond. In someembodiments of a compound of Formula (VI), L is —C(═O)—.

In some embodiments of a compound of Formula (VI), Ring A isheterocycloalkyl or heteroaryl; each optionally substituted with one ormore R^(A). In some embodiments of a compound of Formula (VI), Ring A isa 5-membered heterocycloalkyl or a 5-membered heteroaryl; eachoptionally substituted with one or more R^(A). In some embodiments of acompound of Formula (VI), Ring A is heteroaryl optionally substitutedwith one or more R^(A).

In some embodiments of a compound of Formula (VI), each R^(A) isindependently deuterium, halogen, —CN, —OR^(b), —NR^(c)R^(d),—C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d), —OC(═O)NR^(c)R^(d),C₁-C₆alkyl, C₁-C₆haloalkyl, or C₁-C₆deuteroalkyl. In some embodiments ofa compound of Formula (VI), each R^(A) is independently deuterium,halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, or C₁-C₆deuteroalkyl. In someembodiments of a compound of Formula (VI), each R^(A) is independentlyhalogen or C₁-C₆alkyl. In some embodiments of a compound of Formula(VI), each R^(A) is independently C₁-C₆alkyl.

In some embodiments of a compound of Formula (VI), R⁴ is hydrogen,deuterium, halogen, —CN, —OR^(b), —NR^(c)R^(d), —C(═O)R^(a),—C(═O)OR^(b), —C(═O)NR^(c)R^(d), —OC(═O)NR^(c)R^(d), C₁-C₆alkyl,C₁-C₆haloalkyl, or C₁-C₆deuteroalkyl. In some embodiments of a compoundof Formula (VI), R⁴ is hydrogen or —OR^(b). In some embodiments of acompound of Formula (VI), R⁴ is —OR^(b). In some embodiments of acompound of Formula (VI), R⁴ is hydrogen.

In some embodiments of a compound of Formula (VI), X is —CH—. In someembodiments of a compound of Formula (VI), X is —N—.

In some embodiments of a compound of Formula (VI), the compound is ofFormula (VIa):

In some embodiments of a compound of Formula (VI), the compound is ofFormula (VIb):

In some embodiments of a compound of Formula (VI), (VIa), or (VIb), R³is hydrogen or C₁-C₆alkyl. In some embodiments of a compound of Formula(VI), (VIa), or (VIb), R³ is hydrogen.

In some embodiments of a compound of Formula (VI), (VIa), or (VIb), R¹and R² are independently hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl, orC₁-C₆deuteroalkyl. In some embodiments of a compound of Formula (VI),(VIa), or (VIb), R¹ and R² are independently hydrogen orC₁-C₆deuteroalkyl. In some embodiments of a compound of Formula (VI),(VIa), or (VIb), R¹ is hydrogen. In some embodiments of a compound ofFormula (VI), (VIa), or (VIb), R² is C₁-C₆alkyl or C₁-C₆deuteroalkyl. Insome embodiments of a compound of Formula (VI), (VIa), or (VIb), R² isC₁-C₆deuteroalkyl.

In some embodiments of a compound of Formula (VI), (VIa), or (VIb), L²is a bond.

In some embodiments of a compound of Formula (VI), (VIa), or (VIb), RingE is cycloalkyl, heterocycloalkyl, or aryl, each optionally substitutedwith one or more R^(E).

In some embodiments of a compound of Formula (VI), (VIa), or (VIb), RingF is aryl optionally substituted with one or more R^(E).

In some embodiments of a compound of Formula (VI), (VIa), or (VIb), eachR^(E) is independently deuterium, halogen, —CN, —OR^(b), —NR^(c)R^(d),—C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆alkyl,C₁-C₆haloalkyl, or C₁-C₆deuteroalkyl.

In some embodiments of a compound of Formula (VI), (VIa), or (VIb), eachR^(E) is independently deuterium, halogen, C₁-C₆alkyl, C₁-C₆haloalkyl,or C₁-C₆deuteroalkyl.

In some embodiments of a compound of Formula (VI), (VIa), or (VIb), eachR^(E) is independently halogen.

Also disclosed herein is a compound of Formula (VII), or apharmaceutically acceptable salt, stereoisomer, or solvate thereof:

wherein:

-   -   R¹⁴ is hydrogen, —S(═O)R^(a), —S(═O)₂R^(a), —S(═O)₂NR^(c)R^(d),        —C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,        C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,        C₁-C₆alkyl(cycloalkyl), C₁-C₆alkyl(heterocycloalkyl),        C₁-C₆alkyl(aryl), C₁-C₆alkyl(heteroaryl), cycloalkyl, or        heterocycloalkyl;    -   R³ is hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl, or        C₁-C₆deuteroalkyl;    -   R⁴ is hydrogen, deuterium, halogen, —CN, —OR^(b), —SR^(b),        —S(═O)R^(a), —S(═O)₂R^(a), —NO₂, —NR^(c)R^(d), —NHS(═O)₂R^(a),        —S(═O)₂NR^(c)R^(d), —C(═O)R^(a), —OC(═O)R^(a), —C(═O)OR^(b),        —OC(═O)OR^(b), —C(═O)NR^(c)R^(d), —OC(═O)NR^(c)R^(d),        —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a), —NR^(b)C(═O)OR^(b),        C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl,        C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₂-C₆alkenyl, or        C₂-C₆alkynyl;    -   or R³ and R⁴ are taken together to form an optionally        substituted ring;    -   L is a bond or —C(═O)—;    -   Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;        each optionally substituted with one or more R^(A);    -   each R^(A) is independently deuterium, halogen, —CN, —OR^(b),        —SR^(b), —S(═O)R^(a), —S(═O)₂R^(a), —NO₂, —NR^(c)R^(d),        —NHS(═O)₂R^(a), —S(═O)₂NR^(c)R^(d), —C(═O)R^(a), —OC(═O)R^(a),        —C(═O)OR^(b), —OC(═O)OR^(b), —C(═O)NR^(c)R^(d),        —OC(═O)NR^(c)R^(d), —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a),        —NR^(b)C(═O)OR^(b), C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,        C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl,        or heteroaryl; wherein each alkyl, alkenyl, alkenyl, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl is independently        optionally substituted with one or more oxo, deuterium, halogen,        —CN, —OR^(b), —NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b),        —C(═O)NR^(c)R^(d), C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   or two R^(A) on the same carbon are taken together to form an        oxo;    -   X is —CR^(x)— or —N—;    -   R^(x) is hydrogen, deuterium, halogen, —CN, —OR^(b), —SR^(b),        —S(═O)R^(a), —S(═O)₂R^(a), —NO₂, —NR^(c)R^(d), —NHS(═O)₂R^(a),        —S(═O)₂NR^(c)R^(d), —C(═O)R^(a), —OC(═O)R^(a), —C(═O)OR^(b),        —OC(═O)OR^(b), —C(═O)NR^(c)R^(d), —OC(═O)NR^(c)R^(d),        —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a), —NR^(b)C(═O)OR^(b),        C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl,        C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₂-C₆alkenyl, or        C₂-C₆alkynyl;    -   each R^(a) is independently C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,        C₂-C₆alkenyl, C₁-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl,        or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl is independently        optionally substituted with one or more oxo, deuterium, halogen,        —CN, —OH, OMe, —NH₂, —C(═O)Me, —C(═OOH, —C(═O)OMe, C₁-C₆alkyl,        or C₁-C₆haloalkyl;    -   R⁵ is halogen, —CN, —OR⁸, —SR⁸, —S(═O)R⁷, —S(═O)₂R⁷, —NO₂,        —NHS(═O)₂R⁷, —S(═O)₂NR^(c)R^(d), —C(═O)R⁷, —OC(═O)R⁷, —C(═O)OR⁸,        —OC(═O)OR⁸, —C(═O)NR⁹R¹⁰, —OC(═O)NR⁹R¹⁰, —NR⁸C(═O)NR⁹R¹⁰,        —NR⁸C(═O)R⁷, —NR⁸C(═O)OR⁸, C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,        C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl,        or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl is independently        optionally substituted with one or more oxo, deuterium, halogen,        —CN, —OR^(b), —NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b),        —C(═O)NR^(c)R^(d), C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   or R^(x) and R⁵ are taken together to form ring D optionally        substituted with one or more R^(D);    -   Ring D is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;    -   each R^(D) is independently hydrogen, deuterium, halogen, —CN,        —OR^(b), —SR^(b), —S(═O)R^(a), —S(═O)₂R^(a), —NO₂, —NR^(c)R^(d),        —NHS(═O)₂R^(a), —S(═O)₂NR^(c)R^(d), —C(═O)R^(a), —OC(═O)R^(a),        —C(═O)OR^(b), —OC(═O)OR^(b), —C(═O)NR^(c)R^(d),        —OC(═O)NR^(c)R^(d), —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a),        —NR^(b)C(═O)OR^(b), C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,        C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl,        or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl is independently        optionally substituted with one or more oxo, deuterium, halogen,        —CN, —OR^(b), —NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b),        —C(═O)NR^(c)R^(d), C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   or two R^(D) on the same carbon are taken together to form an        oxo;    -   R⁷ is C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl,        C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,        cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each        alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one or        more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH₂, —C(═O)Me,        —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   each R⁸ is independently hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,        C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl,        or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl is independently        optionally substituted with one or more oxo, deuterium, halogen,        —CN, —OH, —OMe, —NH₂, —C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl,        or C₁-C₆haloalkyl;    -   R⁹ and R¹⁰ are independently hydrogen, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,        C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl,        alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one or        more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH₂, —C(═O)Me,        —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   or R⁹ and R¹⁰ are taken together with the nitrogen atom to which        they are attached to form a heterocycloalkyl optionally        substituted with one or more oxo, deuterium, halogen, —CN, —OH,        —OMe, —NH₂, —C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or        C₁-C₆haloalkyl;    -   each R^(b) is independently hydrogen, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,        C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl,        alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one or        more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH₂, —C(═O)Me,        —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   each R^(c) and R^(d) is independently hydrogen, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,        C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl,        alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one or        more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH₂, —C(═O)Me,        —C(═O)OH, —C(—O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   or R^(c) and R^(d) are taken together with the nitrogen atom to        which they are attached to form a heterocycloalkyl optionally        substituted with one or more oxo, deuterium, halogen, —CN, —OH,        —OMe, —NH₂, —C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or        C₁-C₆haloalkyl.

In some embodiments of a compound of Formula (VII), L is a bond. In someembodiments of a compound of Formula (VII), L is —C(═O)—.

In some embodiments of a compound of Formula (VII), Ring A isheterocycloalkyl or heteroaryl; each optionally substituted with one ormore R^(A). In some embodiments of a compound of Formula (VII), Ring Ais a 5-membered heterocycloalkyl or a 5-membered heteroaryl; eachoptionally substituted with one or more R^(A). In some embodiments of acompound of Formula (VII), Ring A is heteroaryl optionally substitutedwith one or more R^(A).

In some embodiments of a compound of Formula (VII), each R^(A) isindependently deuterium, halogen, —CN, —OR^(b), —NR^(c)R^(d),—C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d), —OC(═O)NR^(c)R^(d),C₁-C₆alkyl, C₁-C₆haloalkyl, or C₁-C₆deuteroalkyl. In some embodiments ofa compound of Formula (VII), each R^(A) is independently deuterium,halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, or C₁-C₆deuteroalkyl. In someembodiments of a compound of Formula (VII), each R^(A) is independentlyhalogen or C₁-C₆alkyl. In some embodiments of a compound of Formula(VII), each R^(A) is independently C₁-C₆alkyl.

In some embodiments of a compound of Formula (VII), R⁴ is hydrogen,deuterium, halogen, —CN, —OR^(b), NR^(c)R^(d), —C(═O)R^(a),—C(═O)OR^(b), —C(═O)NR^(c)R^(d), —OC(═O)NR^(c)R^(d), C₁-C₆alkyl,C₁-C₆haloalkyl, or C₁-C₆deuteroalkyl. In some embodiments of a compoundof Formula (VII), R⁴ is hydrogen or —OR^(b). In some embodiments of acompound of Formula (VII), R⁴ is —OR^(b). In some embodiments of acompound of Formula (VII), R⁴ is hydrogen.

In some embodiments of a compound of Formula (VII), X is —CH—. In someembodiments of a compound of Formula (VII), X is —N—.

In some embodiments of a compound of Formula (VII), the compound is ofFormula (VIIa):

In some embodiments of a compound of Formula (VII), the compound is ofFormula (VIIb):

In some embodiments of a compound of Formula (VII), (VIIa), or (VIIb),R³ is hydrogen or C₁-C₆alkyl. In some embodiments of a compound ofFormula (VII), (VIIa), or (VIIb), R³ is hydrogen.

In some embodiments of a compound of Formula (VII), (VIIa), or (VIIb),R⁵ is halogen, —CN, —OR⁸, —NR⁹R¹⁰, —C(═O)R⁷, —C(═O)OR⁸, —C(═O)NRR¹⁰,—NR⁸C(═O)NR⁹R¹⁰, —NR⁸C(═O)R⁷, —NR⁸C(═O)OR⁸, C₁-C₆alkyl, C₁-C₆haloalkyl,C₁-C₆deuteroalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl,heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is independently optionallysubstituted with one or more oxo, deuterium, halogen, —CN, —OR^(b),—NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆alkyl,or C₁-C₆haloalkyl.

In some embodiments of a compound of Formula (VII), (VIIa), or (VIIb),R⁵ is —OR⁸, —NR⁹R¹⁰, —C(═O)R⁷, —C(═O)OR⁸, —C(═O)NR⁹R¹⁰, —NR⁸C(═O)NR⁹R¹⁰,—NR⁸C(═O)R⁷, —NR⁸C(═O)OR⁸, cycloalkyl, heterocycloalkyl, aryl, orheteroaryl; wherein each cycloalkyl, heterocycloalkyl, aryl, andheteroaryl is independently optionally substituted with one or more oxo,deuterium, halogen, —CN, —OR^(b), —NR^(c)R^(d), —C(═O)R^(a),—C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆alkyl, or C₁-C₆haloalkyl.

In some embodiments of a compound of Formula (VII), (VIIa), or (VIIb),R⁵ is —OR⁸, —NR⁹R¹⁰, —NR⁸C(═O)R⁷,l or aryl optionally substituted withone or more oxo, deuterium, halogen, —CN, —OR^(b), —NR^(c)R^(d),—C(═O)R^(a), —C(═O)OR⁸, —C(═O)NR^(c)R^(d), C₁-C₆alkyl, orC₁-C₆haloalkyl.

In some embodiments of a compound of Formula (VII), (VIIa), or (VIIb),R⁵ is —OR⁸, —NR⁹R¹⁰, —NR⁸C(═O)R⁷, cycloalkyl, heterocycloalkyl, aryl, orheteroaryl; wherein each cycloalkyl, heterocycloalkyl, aryl, andheteroaryl is independently optionally substituted with one or more oxo,deuterium, halogen, —CN, —OR^(b), —NR^(c)R^(d), —C(═O)R^(a),—C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆alkyl, or C₁-C₆haloalkyl. In someembodiments of a compound of Formula (VII), (VIIa), or (VIIb), R⁵ is—NR⁸C(═O)R⁷. In some embodiments of a compound of Formula (VII), (VIIa),or (VIIb), R⁵ is aryl optionally substituted with one or more oxo,deuterium, halogen, —CN, —OR^(b), —NR^(c)R^(d), —C(═O)R^(a),—C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆alkyl, or C₁-C₆haloalkyl.

In some embodiments of a compound of Formula (VII), (VIIa), or (VIIb),R⁷ is C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, cycloalkyl,heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is independently optionallysubstituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe,—NH₂, —C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl. Insome embodiments of a compound of Formula (VII), (VIIa), or (VIIb), R⁷is C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, or cycloalkyl; whereineach alkyl, cycloalkyl, and heterocycloalkyl is independently optionallysubstituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe,—NH₂, —C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl. Insome embodiments of a compound of Formula (VII), (VIIa), or (VIIb), R⁷is cycloalkyl optionally substituted with one or more oxo, deuterium,halogen, —CN, —OH, —OMe, —NH₂, —C(═O)Me, —C(═O)OH, —C(═O)OMe,C₁-C₆alkyl, or C₁-C₆haloalkyl. In some embodiments of a compound ofFormula (VII), (VIIa), or (VIIb), R⁷ is unsubstituted cycloalkyl.

In some embodiments of a compound of Formula (VII), (VIIa), or (VIIb),R⁸ is hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl,cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl,cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independentlyoptionally substituted with one or more oxo, deuterium, halogen, —CN,—OH, —OMe, —C(═O)Me, —C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl. In someembodiments of a compound of Formula (VII), (VIIa), or (VIIb), R⁸ ishydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, or cycloalkyl;wherein each alkyl, cycloalkyl, and heterocycloalkyl is independentlyoptionally substituted with one or more oxo, deuterium, halogen, —CN,—OH, —OMe, —NH₂, —C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, orC₁-C₆haloalkyl.

In some embodiments of a compound of Formula (VII), (VIIa), or (VIIb),R⁹ and R¹⁰ are independently hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl,C₁-C₆deuteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroarylis independently optionally substituted with one or more oxo, deuterium,halogen, —CN, —OH, —OMe, —C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, orC₁-C₆haloalkyl. In some embodiments of a compound of Formula (VII),(VIIa), or (VIIb), R⁹ and R¹⁰ are independently hydrogen, C₁-C₆alkyl,C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, or cycloalkyl; wherein each alkyl,cycloalkyl, and heterocycloalkyl is independently optionally substitutedwith one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH₂,—C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl.

In some embodiments of a compound of Formula (VII), (VIIa), or (VIIb),R¹⁴ is hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, orC₁-C₆alkyl(cycloalkyl). In some embodiments of a compound of Formula(VII), (VIIa), or (VIIb), R¹⁴ is C₁-C₆alkyl or C₁-C₆alkyl(cycloalkyl).

Also disclosed herein is a compound of Formula (VIII), or apharmaceutically acceptable salt, stereoisomer, or solvate thereof:

wherein:

-   -   R¹⁵ is C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl,        C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,        cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each        alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one or        more oxo, deuterium, halogen, —CN, —OR^(b), —NR^(c)R^(d),        —C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆alkyl, or        C₁-C₆haloalkyl;    -   L³ is —O—, —NH—, or —N(CH₃)—;    -   L⁴ is —NR³— or —C(═O)—;    -   R³ is hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl, or        C₁-C₆deuteroalkyl;    -   R⁴ is hydrogen, deuterium, halogen, —CN, —OR^(b), —SR^(b),        —S(═O)R^(a), —S(═O)₂R^(a), —NO₂, —NR^(c)R^(d), —NHS(═O)₂R^(a),        —S(═O)₂NR^(c)R^(d), —C(═O)R^(a), —OC(═O)R^(a), —C(═O)OR^(b),        —OC(═O)OR^(b), —C(═O)NR^(c)R^(d), —OC(═O)NR^(c)R^(d),        —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a), —NR^(b)C(═O)OR^(b),        C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl,        C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₂-C₆alkenyl, or        C₂-C₆alkynyl;    -   or R³ and R⁴ are taken together to form an optionally        substituted ring;    -   L is a bond or —C(═O)—;    -   Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;        each optionally substituted with one or more R^(A);    -   each R^(A) is independently deuterium, halogen, —CN, —OR^(b),        —SR^(b), —S(═O)R^(a), —S(═O)₂R^(a), —NO₂, —NR^(c)R^(d),        —NHS(═O)₂R^(a), —S(═O)₂NR^(c)R^(d), —C(═O)R^(a), —OC(═O)R^(a),        —C(═O)OR^(b), —OC(═O)OR^(b), —C(═O)NR^(c)R^(d),        —OC(═O)NR^(c)R^(d), —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a),        —NR^(b)C(═O)OR^(b), C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,        C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl,        or heteroaryl; wherein each alkyl, alkenyl, alkenyl, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl is independently        optionally substituted with one or more oxo, deuterium, halogen,        —CN, —OR^(b), —NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b),        —C(═O)NR^(c)R^(d), C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   or two R^(A) on the same carbon are taken together to form an        oxo;    -   X is —CR^(x)— or —N—;    -   R^(x) is hydrogen, deuterium, halogen, —CN, —OR^(b), —SR^(b),        —S(═O)R^(a), —S(═O)₂R^(a), —NO₂, —NR^(c)R^(d), —NHS(═O)₂R^(a),        —S(═O)₂NR^(c)R^(d), —C(═O)R^(a), —OC(═O)R^(a), —C(═O)OR^(b),        —OC(═O)OR^(b), —C(═O)NR^(c)R^(d), —OC(═O)NR^(c)R^(d),        —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a), —NR^(b)C(═O)OR^(b),        C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl,        C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₂-C₆alkenyl, or        C₂-C₆alkynyl;    -   each R^(a) is independently C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,        C₂-C₆alkenyl, C₁-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl,        or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl is independently        optionally substituted with one or more oxo, deuterium, halogen,        —CN, —OH, OMe, —NH₂, —C(═O)Me, —C(═OOH, —C(═O)OMe, C₁-C₆alkyl,        or C₁-C₆haloalkyl;    -   R⁵ is halogen, —CN, —OR⁸, —SR⁸, —S(═O)R⁷, —S(═O)₂R⁷, —NO₂,        —NHS(═O)₂R⁷, —S(═O)₂NR^(c)R^(d), —C(═O)R⁷, —OC(═O)R⁷, —C(═O)OR⁸,        —OC(═O)OR⁸, —C(═O)NR⁹R¹⁰, —OC(═O)NR⁹R¹⁰, —NR⁸C(═O)NR⁹R¹⁰,        —NR⁸C(═O)R⁷, —NR⁸C(═O)OR⁸, C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,        C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl,        or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl is independently        optionally substituted with one or more oxo, deuterium, halogen,        —CN, —OR^(b), —NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b),        —C(═O)NR^(c)R^(d), C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   or R^(x) and R⁵ are taken together to form ring D optionally        substituted with one or more R^(D);    -   Ring D is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;    -   each R^(D) is independently hydrogen, deuterium, halogen, —CN,        —OR^(b), —SR^(b), —S(═O)R^(a), —S(═O)₂R^(a), —NO₂, —NR^(c)R^(d),        —NHS(═O)₂R^(a), —S(═O)₂NR^(c)R^(d), —C(═O)R^(a), —OC(═O)R^(a),        —C(═O)OR^(b), —OC(═O)OR^(b), —C(═O)NR^(c)R^(d),        —OC(═O)NR^(c)R^(d), —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a),        —NR^(b)C(═O)OR^(b), C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,        C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl,        or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl is independently        optionally substituted with one or more oxo, deuterium, halogen,        —CN, —OR^(b), —NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b),        —C(═O)NR^(c)R^(d), C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   or two R^(D) on the same carbon are taken together to form an        oxo;    -   R⁷ is C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl,        C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,        cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each        alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one or        more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH₂, —C(═O)Me,        —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   each R⁸ is independently hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,        C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl,        or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl is independently        optionally substituted with one or more oxo, deuterium, halogen,        —CN, —OH, —OMe, —NH₂, —C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl,        or C₁-C₆haloalkyl;    -   R⁹ and R¹⁰ are independently hydrogen, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,        C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl,        alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one or        more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH₂, —C(═O)Me,        —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   or R⁹ and R¹⁰ are taken together with the nitrogen atom to which        they are attached to form a heterocycloalkyl optionally        substituted with one or more oxo, deuterium, halogen, —CN, —OH,        —OMe, —NH₂, —C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or        C₁-C₆haloalkyl;    -   each R^(b) is independently hydrogen, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,        C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl,        alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one or        more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH₂, —C(═O)Me,        —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   each R^(c) and R^(d) is independently hydrogen, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,        C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl,        alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one or        more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH₂, —C(═O)Me,        —C(═O)OH, —C(—O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   or R^(c) and R^(d) are taken together with the nitrogen atom to        which they are attached to form a heterocycloalkyl optionally        substituted with one or more oxo, deuterium, halogen, —CN, —OH,        —OMe, —NH₂, —C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or        C₁-C₆haloalkyl.

In some embodiments of a compound of Formula (VIII), L is a bond. Insome embodiments of a compound of Formula (VIII), L is —C(═O)—.

In some embodiments of a compound of Formula (VIII), Ring A isheterocycloalkyl or heteroaryl; each optionally substituted with one ormore R^(A). In some embodiments of a compound of Formula (VIII), Ring Ais a 5-membered heterocycloalkyl or a 5-membered heteroaryl; eachoptionally substituted with one or more R^(A). In some embodiments of acompound of Formula (VIII), Ring A is heteroaryl optionally substitutedwith one or more R^(A).

In some embodiments of a compound of Formula (VIII), each R^(A) isindependently deuterium, halogen, —CN, —OR^(b), —NR^(c)R^(d),—C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d), —OC(═O)NR^(c)R^(d),C₁-C₆alkyl, C₁-C₆haloalkyl, or C₁-C₆deuteroalkyl. In some embodiments ofa compound of Formula (VIII), each R^(A) is independently deuterium,halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, or C₁-C₆deuteroalkyl. In someembodiments of a compound of Formula (VIII), each R^(A) is independentlyhalogen or C₁-C₆alkyl. In some embodiments of a compound of Formula(VIII), each R^(A) is independently C₁-C₆alkyl.

In some embodiments of a compound of Formula (VIII), R⁴ is hydrogen,deuterium, halogen, —CN, —OR^(b), NR^(c)R^(d), —C(═O)R^(a),—C(═O)OR^(b), —C(═O)NR^(c)R^(d), —OC(═O)NR^(c)R^(d), C₁-C₆alkyl,C₁-C₆haloalkyl, or C₁-C₆deuteroalkyl. In some embodiments of a compoundof Formula (VIII), R⁴ is hydrogen or —OR^(b). In some embodiments of acompound of Formula (VIII), R⁴ is —OR^(b). In some embodiments of acompound of Formula (VIII), R⁴ is hydrogen.

In some embodiments of a compound of Formula (VIII), X is —CH—. In someembodiments of a compound of Formula (VIII), X is —N—.

In some embodiments of a compound of Formula (VIII), the compound is ofFormula (VIIIa):

In some embodiments of a compound of Formula (VIII), the compound is ofFormula (VIIIb):

In some embodiments of a compound of Formula (VIII), (VIIIa), or(VIIIb), R⁵ is halogen, —CN, —OR⁸, —NR⁹R¹⁰, —C(═O)R⁷, —C(═O)OR⁸,—C(═O)NRR¹⁰, —NR⁸C(═O)NR⁹R¹⁰, —NR⁸C(═O)R⁷, —NR⁸C(═O)OR⁸, C₁-C₆alkyl,C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl,cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independentlyoptionally substituted with one or more oxo, deuterium, halogen, —CN,—OR^(b), —NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d),C₁-C₆alkyl, or C₁-C₆haloalkyl.

In some embodiments of a compound of Formula (VIII), (VIIIa), or(VIIIb), R⁵ is —OR⁸, —NR⁹R¹⁰, —C(═O)R⁷, —C(═O)OR⁸, —C(═O)NR⁹R¹⁰,—NR⁸C(═O)NR⁹R¹⁰, —NR⁸C(═O)R⁷, —NR⁸C(═O)OR⁸, cycloalkyl,heterocycloalkyl, aryl, or heteroaryl; wherein each cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is independently optionallysubstituted with one or more oxo, deuterium, halogen, —CN, —OR^(b),—NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆alkyl,or C₁-C₆haloalkyl.

In some embodiments of a compound of Formula (VIII), (VIIIa), or(VIIIb), R⁵ is —OR⁸, —NR⁹R¹⁰, —NR⁸C(═O)R⁷,l or aryl optionallysubstituted with one or more oxo, deuterium, halogen, —CN, —OR^(b),—NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR⁸, —C(═O)NR^(c)R^(d), C₁-C₆alkyl, orC₁-C₆haloalkyl.

In some embodiments of a compound of Formula (VIII), (VIIIa), or(VIIIb), R⁵ is —OR⁸, —NR⁹R¹⁰, —NR⁸C(═O)R⁷, cycloalkyl, heterocycloalkyl,aryl, or heteroaryl; wherein each cycloalkyl, heterocycloalkyl, aryl,and heteroaryl is independently optionally substituted with one or moreoxo, deuterium, halogen, —CN, —OR^(b), —NR^(c)R^(d), —C(═O)R^(a),—C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆alkyl, or C₁-C₆haloalkyl. In someembodiments of a compound of Formula (VIII), (VIIIa), or (VIIIb), R⁵ is—NR⁸C(═O)R⁷. In some embodiments of a compound of Formula (VIII),(VIIIa), or (VIIIb), R⁵ is aryl optionally substituted with one or moreoxo, deuterium, halogen, —CN, —OR^(b), —NR^(c)R^(d), —C(═O)R^(a),—C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆alkyl, or C₁-C₆haloalkyl.

In some embodiments of a compound of Formula (VIII), (VIIIa), or(VIIIb), R⁷ is C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl,cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl,cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independentlyoptionally substituted with one or more oxo, deuterium, halogen, —CN,—OH, —OMe, —NH₂, —C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, orC₁-C₆haloalkyl. In some embodiments of a compound of Formula (VIII),(VIIIa), or (VIIIb), R⁷ is C₁-C₆alkyl, C₁-C₆haloalkyl,C₁-C₆deuteroalkyl, or cycloalkyl; wherein each alkyl, cycloalkyl, andheterocycloalkyl is independently optionally substituted with one ormore oxo, deuterium, halogen, —CN, —OH, —OMe, —NH₂, —C(═O)Me, —C(═O)OH,—C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl. In some embodiments of acompound of Formula (VIII), (VIIIa), or (VIIIb), R⁷ is cycloalkyloptionally substituted with one or more oxo, deuterium, halogen, —CN,—OH, —OMe, —NH₂, —C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, orC₁-C₆haloalkyl. In some embodiments of a compound of Formula (VIII),(VIIIa), or (VIIIb), R⁷ is unsubstituted cycloalkyl.

In some embodiments of a compound of Formula (VIII), (VIIIa), or(VIIIb), R⁸ is hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl,cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl,cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independentlyoptionally substituted with one or more oxo, deuterium, halogen, —CN,—OH, —OMe, —C(═O)Me, —C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl. In someembodiments of a compound of Formula (VIII), (VIIIa), or (VIIIb), R⁸ ishydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, or cycloalkyl;wherein each alkyl, cycloalkyl, and heterocycloalkyl is independentlyoptionally substituted with one or more oxo, deuterium, halogen, —CN,—OH, —OMe, —NH₂, —C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, orC₁-C₆haloalkyl.

In some embodiments of a compound of Formula (VIII), (VIIIa), or(VIIIb), R⁹ and R¹⁰ are independently hydrogen, C₁-C₆alkyl,C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, cycloalkyl, heterocycloalkyl, aryl,or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl,and heteroaryl is independently optionally substituted with one or moreoxo, deuterium, halogen, —CN, —OH, —OMe, —C(═O)Me, —C(═O)OH, —C(═O)OMe,C₁-C₆alkyl, or C₁-C₆haloalkyl. In some embodiments of a compound ofFormula (VIII), (VIIIa), or (VIIIb), R⁹ and R¹⁰ are independentlyhydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, or cycloalkyl;wherein each alkyl, cycloalkyl, and heterocycloalkyl is independentlyoptionally substituted with one or more oxo, deuterium, halogen, —CN,—OH, —OMe, —NH₂, —C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, orC₁-C₆haloalkyl.

In some embodiments of a compound of Formula (VIII), (VIIIa), or(VIIIb), L³ is —O—. In some embodiments of a compound of Formula (VIII),(VIIIa), or (VIIIb), L³ is —NH—.

In some embodiments of a compound of Formula (VIII), (VIIIa), or(VIIIb), R¹⁵ is C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, orcycloalkyl.

In some embodiments of a compound of Formula (VIII), (VIIIa), or(VIIIb), L⁴ is —NR³—.

In some embodiments of a compound of Formula (VIII), (VIIIa), or(VIIIb), R³ is hydrogen or C₁-C₆alkyl. In some embodiments of a compoundof Formula (VIII), (VIIIa), or (VIIIb), R³ is hydrogen.

In some embodiments of a compound of Formula (VIII), (VIIIa), or(VIIIb), L⁴ is —C(═O)—.

A compound of Formula (IX), or a pharmaceutically acceptable salt,stereoisomer, or solvate thereof:

wherein:

-   -   Ring F is a heterocycloalkyl or heteroaryl;    -   each R^(F) is independently hydrogen, deuterium, halogen, —CN,        —OR^(b), —SR^(b), —S(═O)R^(a), —S(═O)₂R^(a), —NO₂, —NR^(c)R^(d),        —NHS(═O)₂R^(a), —S(═O)₂NR^(c)R^(d), —C(═O)R^(a), —OC(═O)R^(a),        —C(═O)OR^(b), —OC(═O)OR^(b), —C(═O)NR^(c)R^(d),        —OC(═O)NR^(c)R^(d), —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a),        —NR^(b)C(═O)OR^(b), C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆alkenyl, or        C₁-C₆alkynyl;    -   or two R^(F) on the same carbon are taken together to form an        oxo;    -   or two R^(F) on adjacent atoms are taken together to form a        cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each        optionally substituted with one or more deuterium, oxo, halogen,        —CN, —OR^(b), —NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b),        —C(═O)NR^(c)R^(d), C₁-C₆alkyl, C₁-C₆deuteroalkyl, or        C₁-C₆haloalkyl;    -   p is 0-4;    -   R³ is hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl, or        C₁-C₆deuteroalkyl;    -   R⁴ is hydrogen, deuterium, halogen, —CN, —OR^(b), —SR^(b),        —S(═O)R^(a), —S(═O)₂R^(a), —NO₂, —NR^(c)R^(d), —NHS(═O)₂R^(a),        —S(═O)₂NR^(c)R^(d), —C(═O)R^(a), —OC(═O)R^(a), —C(═O)OR^(b),        —OC(═O)OR^(b), —C(═O)NR^(c)R^(d), —OC(═O)NR^(c)R^(d),        —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a), —NR^(b)C(═O)OR^(b),        C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl,        C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₂-C₆alkenyl, or        C₂-C₆alkynyl;    -   or R³ and R⁴ are taken together to form an optionally        substituted ring;    -   L is a bond or —C(═O)—;    -   Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;        each optionally substituted with one or more R^(A);    -   each R^(A) is independently deuterium, halogen, —CN, —OR^(b),        —SR^(b), —S(═O)R^(a), —S(═O)₂R^(a), —NO₂, —NR^(c)R^(d),        —NHS(═O)₂R^(a), —S(═O)₂NR^(c)R^(d), —C(═O)R^(a), —OC(═O)R^(a),        —C(═O)OR^(b), —OC(═O)OR^(b), —C(═O)NR^(c)R^(d),        —OC(═O)NR^(c)R^(d), —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a),        —NR^(b)C(═O)OR^(b), C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,        C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl,        or heteroaryl; wherein each alkyl, alkenyl, alkenyl, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl is independently        optionally substituted with one or more oxo, deuterium, halogen,        —CN, —OR^(b), —NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b),        —C(═O)NR^(c)R^(d), C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   or two R^(A) on the same carbon are taken together to form an        oxo;    -   X is —CR^(x)— or —N—;    -   R^(x) is hydrogen, deuterium, halogen, —CN, —OR^(b), —SR^(b),        —S(═O)R^(a), —S(═O)₂R^(a), —NO₂, —NR^(c)R^(d), —NHS(═O)₂R^(a),        —S(═O)₂NR^(c)R^(d), —C(═O)R^(a), —OC(═O)R^(a), —C(═O)OR^(b),        —OC(═O)OR^(b), —C(═O)NR^(c)R^(d), —OC(═O)NR^(c)R^(d),        —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a), —NR^(b)C(═O)OR^(b),        C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl,        C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₂-C₆alkenyl, or        C₂-C₆alkynyl;    -   R⁵ is halogen, —CN, —OR⁸, —SR⁸, —S(═O)R⁷, —S(═O)₂R⁷, —NO₂,        —NHS(═O)₂R⁷, —S(═O)₂NR^(c)R^(d), —C(═O)R⁷, —OC(═O)R⁷, —C(═O)OR⁸,        —OC(═O)OR⁸, —C(═O)NR⁹R¹⁰, —OC(═O)NR⁹R¹⁰, —NR⁸C(═O)NR⁹R¹⁰,        —NR⁸C(═O)R⁷, —NR⁸C(═O)OR⁸, C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,        C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl,        or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl is independently        optionally substituted with one or more oxo, deuterium, halogen,        —CN, —OR^(b), —NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b),        —C(═O)NR^(c)R^(d), C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   or R^(x) and R⁵ are taken together to form ring D optionally        substituted with one or more R^(D);    -   Ring D is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;    -   each R^(D) is independently hydrogen, deuterium, halogen, —CN,        —OR^(b), —SR^(b), —S(═O)R^(a), —S(═O)₂R^(a), —NO₂, —NR^(c)R^(d),        —NHS(═O)₂R^(a), —S(═O)₂NR^(c)R^(d), —C(═O)R^(a), —OC(═O)R^(a),        —C(═O)OR^(b), —OC(═O)OR^(b), —C(═O)NR^(c)R^(d),        —OC(═O)NR^(c)R^(d), —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a),        —NR^(b)C(═O)OR^(b), C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,        C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl,        or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl is independently        optionally substituted with one or more oxo, deuterium, halogen,        —CN, —OR^(b), —NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b),        —C(═O)NR^(c)R^(d), C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   or two R^(D) on the same carbon are taken together to form an        oxo;    -   R⁷ is C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl,        C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,        cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each        alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one or        more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH₂, —C(═O)Me,        —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   each R⁸ is independently hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,        C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl,        or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl is independently        optionally substituted with one or more oxo, deuterium, halogen,        —CN, —OH, —OMe, —NH₂, —C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl,        or C₁-C₆haloalkyl;    -   R⁹ and R¹⁰ are independently hydrogen, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,        C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl,        alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one or        more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH₂, —C(═O)Me,        —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   or R⁹ and R¹⁰ are taken together with the nitrogen atom to which        they are attached to form a heterocycloalkyl optionally        substituted with one or more oxo, deuterium, halogen, —CN, —OH,        —OMe, —NH₂, —C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or        C₁-C₆haloalkyl;    -   each R^(a) is independently C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,        C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl,        or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl is independently        optionally substituted with one or more oxo, deuterium, halogen,        —CN, —OH, —OMe, —NH₂, —C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl,        or C₁-C₆haloalkyl;    -   each R^(b) is independently hydrogen, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,        C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl,        alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one or        more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH₂, —C(═O)Me,        —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   each R^(c) and R^(d) is independently hydrogen, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,        C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl,        alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one or        more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH₂, —C(═O)Me,        —C(═O)OH, —C(—O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   or R^(c) and R^(d) are taken together with the nitrogen atom to        which they are attached to form a heterocycloalkyl optionally        substituted with one or more oxo, deuterium, halogen, —CN, —OH,        —OMe, —NH₂, —C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or        C₁-C₆haloalkyl.

In some embodiments of a compound of Formula (IX), L is a bond. In someembodiments of a compound of Formula (IX), L is —C(═O)—.

In some embodiments of a compound of Formula (IX), Ring A isheterocycloalkyl or heteroaryl; each optionally substituted with one ormore R^(A). In some embodiments of a compound of Formula (IX), Ring A isa 5-membered heterocycloalkyl or a 5-membered heteroaryl; eachoptionally substituted with one or more R^(A). In some embodiments of acompound of Formula (IX), Ring A is heteroaryl optionally substitutedwith one or more R^(A).

In some embodiments of a compound of Formula (IX), each R^(A) isindependently deuterium, halogen, —CN, —OR^(b), —NR^(c)R^(d),—C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d), —OC(═O)NR^(c)R^(d),C₁-C₆alkyl, C₁-C₆haloalkyl, or C₁-C₆deuteroalkyl. In some embodiments ofa compound of Formula (IX), each R^(A) is independently deuterium,halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, or C₁-C₆deuteroalkyl. In someembodiments of a compound of Formula (IX), each R^(A) is independentlyhalogen or C₁-C₆alkyl. In some embodiments of a compound of Formula(IX), each R^(A) is independently C₁-C₆alkyl.

In some embodiments of a compound of Formula (IX), R⁴ is hydrogen,deuterium, halogen, —CN, —OR^(b), NR^(c)R^(d), —C(═O)R^(a),—C(═O)OR^(b), —C(═O)NR^(c)R^(d), —OC(═O)NR^(c)R^(d), C₁-C₆alkyl,C₁-C₆haloalkyl, or C₁-C₆deuteroalkyl. In some embodiments of a compoundof Formula (IX), R⁴ is hydrogen or —OR^(b). In some embodiments of acompound of Formula (IX), R⁴ is —OR^(b). In some embodiments of acompound of Formula (IX), R⁴ is hydrogen.

In some embodiments of a compound of Formula (IX), X is —CH—. In someembodiments of a compound of Formula (IX), X is —N—.

In some embodiments of a compound of Formula (IX), the compound is ofFormula (IXa):

In some embodiments of a compound of Formula (IX), the compound is ofFormula (IXb):

In some embodiments of a compound of Formula (IX), (IXa), or (IXb), R³is hydrogen or C₁-C₆alkyl. In some embodiments of a compound of Formula(IX), (IXa), or (IXb), R³ is hydrogen.

In some embodiments of a compound of Formula (IX), (IXa), or (IXb), R⁵is halogen, —CN, —OR⁸, —NR⁹R¹⁰, —C(═O)R⁷, —C(═O)OR⁸, —C(═O)NRR¹⁰,—NR⁸C(═O)NR⁹R¹⁰, —NR⁸C(═O)R⁷, —NR⁸C(═O)OR⁸, C₁-C₆alkyl, C₁-C₆haloalkyl,C₁-C₆deuteroalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl,heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is independently optionallysubstituted with one or more oxo, deuterium, halogen, —CN, —OR^(b),—NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆alkyl,or C₁-C₆haloalkyl.

In some embodiments of a compound of Formula (IX), (IXa), or (IXb), R⁵is —OR⁸, —NR⁹R¹⁰, —C(═O)R⁷, —C(═O)OR⁸, —C(═O)NR⁹R¹⁰, —NR⁸C(═O)NR⁹R¹⁰,—NR⁸C(═O)R⁷, —NR⁸C(═O)OR⁸, cycloalkyl, heterocycloalkyl, aryl, orheteroaryl; wherein each cycloalkyl, heterocycloalkyl, aryl, andheteroaryl is independently optionally substituted with one or more oxo,deuterium, halogen, —CN, —OR^(b), —NR^(c)R^(d), —C(═O)R^(a),—C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆alkyl, or C₁-C₆haloalkyl.

In some embodiments of a compound of Formula (IX), (IXa), or (IXb), R⁵is —OR⁸, —NR⁹R¹⁰, —NR⁸C(═O)R⁷, or aryl optionally substituted with oneor more oxo, deuterium, halogen, —CN, —OR^(b), —NR^(c)R^(d),—C(═O)R^(a), —C(═O)OR⁸, —C(═O)NR^(c)R^(d), C₁-C₆alkyl, orC₁-C₆haloalkyl.

In some embodiments of a compound of Formula (IX), (IXa), or (IXb), R⁵is —OR⁸, —NR⁹R¹⁰, —NR⁸C(═O)R⁷, cycloalkyl, heterocycloalkyl, aryl, orheteroaryl; wherein each cycloalkyl, heterocycloalkyl, aryl, andheteroaryl is independently optionally substituted with one or more oxo,deuterium, halogen, —CN, —OR^(b), —NR^(c)R^(d), —C(═O)R^(a),—C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆alkyl, or C₁-C₆haloalkyl. In someembodiments of a compound of Formula (IX), (IXa), or (IXb), R⁵ is—NR⁸C(═O)R⁷. In some embodiments of a compound of Formula (IX), (IXa),or (IXb), R⁵ is aryl optionally substituted with one or more oxo,deuterium, halogen, —CN, —OR^(b), —NR^(c)R^(d), —C(═O)R^(a),—C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆alkyl, or C₁-C₆haloalkyl.

In some embodiments of a compound of Formula (IX), (IXa), or (IXb), R⁷is C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, cycloalkyl,heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is independently optionallysubstituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe,—NH₂, —C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl. Insome embodiments of a compound of Formula (IX), (IXa), or (IXb), R⁷ isC₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, or cycloalkyl; whereineach alkyl, cycloalkyl, and heterocycloalkyl is independently optionallysubstituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe,—NH₂, —C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl. Insome embodiments of a compound of Formula (IX), (IXa), or (IXb), R⁷ iscycloalkyl optionally substituted with one or more oxo, deuterium,halogen, —CN, —OH, —OMe, —NH₂, —C(═O)Me, —C(═O)OH, —C(═O)OMe,C₁-C₆alkyl, or C₁-C₆haloalkyl. In some embodiments of a compound ofFormula (IX), (IXa), or (IXb), R⁷ is unsubstituted cycloalkyl.

In some embodiments of a compound of Formula (IX), (IXa), or (IXb), R⁸is hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, cycloalkyl,heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is independently optionallysubstituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe,—C(═O)Me, —C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl. In some embodimentsof a compound of Formula (IX), (IXa), or (IXb), R⁸ is hydrogen,C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, or cycloalkyl; whereineach alkyl, cycloalkyl, and heterocycloalkyl is independently optionallysubstituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe,—NH₂, —C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl.

In some embodiments of a compound of Formula (IX), (IXa), or (IXb), R⁹and R¹⁰ are independently hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl,C₁-C₆deuteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroarylis independently optionally substituted with one or more oxo, deuterium,halogen, —CN, —OH, —OMe, —C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, orC₁-C₆haloalkyl. In some embodiments of a compound of Formula (IX),(IXa), or (IXb), R⁹ and R¹⁰ are independently hydrogen, C₁-C₆alkyl,C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, or cycloalkyl; wherein each alkyl,cycloalkyl, and heterocycloalkyl is independently optionally substitutedwith one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH₂,—C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl.

In some embodiments of a compound of Formula (IX), (IXa), or (IXb), RingF is a heterocycloalkyl.

In some embodiments of a compound of Formula (IX), (IXa), or (IXb),

is

In some embodiments of a. compound of Formula (IX), (IXa), or (IXb),each R^(F) is independently hydrogen, deuterium, halogen, —CN, —OR^(b),—NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆alkyl,C₁-C₆haloalkyl, or C₁-C₆deuteroalkyl. In some embodiments of a compoundof Formula (IX), (IXa), or (IXb), each R^(F) is independently hydrogen,deuterium, halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, or C₁-C₆deuteroalkyl.

In some embodiments of a compound of Formula (IX), (IXa), or (IXb), p is0. In some embodiments of a compound of Formula (IX), (IXa), or (IXb), pis 1. In some embodiments of a compound of Formula (IX), (IXa), or(IXb), p is 2. In some embodiments of a compound of Formula (IX), (IXa),or (IXb), p is 0-2. In some embodiments of a compound of Formula (IX),(IXa), or (IXb), p is 0 or 1. In some embodiments of a compound ofFormula (IX), (IXa), or (IXb), p is 1 or 2. In some embodiments of acompound of Formula (IX), (IXa), or (IXb), p is 1-3.

Also disclosed herein is a compound of Formula (X), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof:

wherein:

-   -   L⁵ is a saturated or unsaturated linear aliphatic chain having        1-10 carbon atoms optionally substituted with one or more        R^(L5), wherein 1-5 carbon atoms are optionally replaced with        —NH—, —N(CH₃)—, —O—, —S—, —S(═O)—, —S(═O)₂—, or —P(═O)—;    -   each R^(L5) is independently deuterium, halogen, —CN, 13 OR^(b),        —SR^(b), —S(═O)R^(a), —S(═O)₂R^(a), —NO₂, —NR^(c)R^(d),        —NHS(═O)₂R_(a), —S(═O)₂NR^(c)R^(d), —C(═O)R^(a), —OC(═O)R^(a),        —OC(═O)OR^(b), —OC(═O)OR^(b), —C(═O)NR^(c)R_(d),        —OC(═O)NR^(c)R^(d), —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a),        —NR^(b)C(═O)OR^(b), C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,        C₂-C₆alkenyl, or C₂-C₆alkynyl;    -   or two R^(L5) on the same carbon atom are taken together to form        an oxo;    -   R¹² is —C(═O)NR¹R² or -L¹—R¹³;    -   R¹ and R² are independently hydrogen, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,        C₁-C₆aminoalkyl, C₂-C₆alkenyl, or C₂-C₆alkynyl;    -   L¹ is —O—, —NH—, or —N(CH₃)—;    -   R¹³ is C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl,        C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,        cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each        alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one or        more oxo, deuterium, halogen, —CN, —OR^(b), —NR^(c)R^(d),        —C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆alkyl, or        C₁-C₆haloalkyl;    -   R³ is hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl, or        C₁-C₆deuteroalkyl;    -   R⁴ is hydrogen, deuterium, halogen, —CN, —OR^(b), —SR^(b),        —S(═O)R^(a), —S(═O)₂R^(a), —NO₂, —NR^(c)R^(d), —NHS(═O)₂R^(a),        —S(═O)₂NR^(c)R^(d), —C(═O)R^(a), —OC(═O)R^(a), —C(═O)OR^(b),        —OC(═O)OR^(b), —C(═O)NR^(c)R^(d), —OC(═O)NR^(c)R^(d),        —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a), —NR^(b)C(═O)OR^(b),        C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl,        C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₂-C₆alkenyl, or        C₂-C₆alkynyl;    -   or R³ and R⁴ are taken together to form an optionally        substituted ring;    -   L is a bond or —C(═O)—;    -   Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;        each optionally substituted with one or more R^(A);    -   each R^(A) is independently deuterium, halogen, —CN, —OR^(b),        —SR^(b), —S(═O)R^(a), —S(═O)₂R^(a), —NO₂, —NR^(c)R^(d),        —NHS(═O)₂R^(a), —S(═O)₂NR^(c)R^(d), —C(═O)R^(a), —OC(═O)R^(a),        —C(═O)OR^(b), —OC(═O)OR^(b), —C(═O)NR^(c)R^(d),        —OC(═O)NR^(c)R^(d), —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a),        —NR^(b)C(═O)OR^(b), C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,        C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl,        or heteroaryl; wherein each alkyl, alkenyl, alkenyl, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl is independently        optionally substituted with one or more oxo, deuterium, halogen,        —CN, —OR^(b), —NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b),        —C(═O)NR^(c)R^(d), C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   or two R^(A) on the same carbon are taken together to form an        oxo;    -   X is —CR^(x)— or —N—;    -   R^(x) is hydrogen, deuterium, halogen, —CN, —OR^(b), —SR^(b),        —S(═O)R^(a), —S(═O)₂R^(a), —NO₂, —NR^(c)R^(d), —NHS(═O)₂R^(a),        —S(═O)₂NR^(c)R^(d), —C(═O)R^(a), —OC(═O)R^(a), —C(═O)OR^(b),        —OC(═O)OR^(b), —C(═O)NR^(c)R^(d), —OC(═O)NR^(c)R^(d),        —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a), —NR^(b)C(═O)OR^(b),        C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl,        C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₂-C₆alkenyl, or        C₂-C₆alkynyl;    -   each R^(a) is independently C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,        C₂-C₆alkenyl, C₁-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl,        or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl is independently        optionally substituted with one or more oxo, deuterium, halogen,        —CN, —OH, OMe, —NH₂, —C(═O)Me, —C(═OOH, —C(═O)OMe, C₁-C₆alkyl,        or C₁-C₆haloalkyl;    -   each R^(b) is independently hydrogen, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,        C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl,        alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one or        more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH₂, —C(═O)Me,        —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   each R^(c) and R^(d) is independently hydrogen, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,        C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl,        alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one or        more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH₂, —C(═O)Me,        —C(═O)OH, —C(—O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   or R^(c) and R^(d) are taken together with the nitrogen atom to        which they are attached to form a heterocycloalkyl optionally        substituted with one or more oxo, deuterium, halogen, —CN, —OH,        —OMe, —NH₂, —C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or        C₁-C₆haloalkyl.

In some embodiments of a compound of Formula (X), L is a bond. In someembodiments of a compound of Formula (X), L is —C(═O)—.

In some embodiments of a compound of Formula (X), Ring A isheterocycloalkyl or heteroaryl; each optionally substituted with one ormore R^(A), In some embodiments of a compound of Formula (X), Ring A isa 5-membered heterocycloalkyl or a 5-membered heteroaryl; eachoptionally substituted with one or more R^(A). In some embodiments of acompound of Formula (X), Ring A is heteroaryl optionally substitutedwith one or more R^(A).

In some embodiments of a compound of Formula (X), each R^(A) isindependently deuterium, halogen, —CN, —OR^(b), —NR^(c)R^(d),—C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d), —OC(═O)NR^(c)R^(d),C₁-C₆alkyl, C₁-C₆haloalkyl, or C₁-C₆deuteroalkyl. In some embodiments ofa compound of Formula (X), each R^(A) is independently deuterium,halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, or C₁-C₆deuteroalkyl. In someembodiments of a compound of Formula (X), each R^(A) is independentlyhalogen or C₁-C₆alkyl. In some embodiments of a compound of Formula (X),each R^(A) is independently C₁-C₆alkyl.

In some embodiments of a compound of Formula (X), R⁴ is hydrogen,deuterium, halogen, —CN, —OR^(b), —NR^(c)R^(d), —C(═O)R^(a),—C(═O)OR^(b), —C(═O)NR^(c)R^(d), —OC(═O)NR^(c)R^(d), C₁-C₆alkyl,C₁-C₆haloalkyl, or C₁-C₆deuteroalkyl. In some embodiments of a compoundof Formula (X), R⁴ is hydrogen or —OR^(b). In some embodiments of acompound of Formula (X), R⁴ is —OR^(b). In some embodiments of acompound of Formula (X), R⁴ is hydrogen.

In some embodiments of a compound of Formula (X), X is —CH—. In someembodiments of a compound of Formula (X), X is —N—.

In some embodiments of a compound of Formula (X), the compound is ofFormula

In some embodiments of a compound of Formula (X), the compound is ofFormula

In some embodiments of a compound of Formula (X), the compound is ofFormula (Xa):

In some embodiments of a compound of Formula (X), the compound is ofFormula (Xb):

In some embodiments of a compound of Formula (X), the compound is ofFormula (Xa-1):

In some embodiments of a compound of Formula (X), the compound is ofFormula (Xb-1):

In some embodiments of a compound of Formula (X), (Xa), (Xa-1), (Xb), or(Xb-1), R³ is hydrogen or C₁-C₆alkyl. In some embodiments of a compoundof Formula (X), (Xa), (Xa-1), (Xb), or (Xb-1), R³ is hydrogen.

In some embodiments of a compound of Formula (X), (Xa), (Xa-1), (Xb), or(Xb-1), R¹² is —C(═O)NR¹R².

In some embodiments of a compound of Formula (X), (Xa), (Xa-1), (Xb), or(Xb-1), R¹ and R² are independently hydrogen, C₁-C₆alkyl,C₁-C₆haloalkyl, or C₁-C₆deuteroalkyl. In some embodiments of a compoundof Formula (X), (Xa), (Xa-1), (Xb), or (Xb-1), R¹ and R² areindependently hydrogen or C₁-C₆deuteroalkyl. In some embodiments of acompound of Formula (X), (Xa), (Xa-1), (Xb), or (Xb-1), R¹ is hydrogen.In some embodiments of a compound of Formula (X), (Xa), (Xa-1), (Xb), or(Xb-1), R² is C₁-C₆alkyl or C₁-C₆deuteroalkyl. In some embodiments of acompound of Formula (X), (Xa), (Xa-1), (Xb), or (Xb-1), R² isC₁-C₆deuteroalkyl.

In some embodiments of a compound of Formula (X), (Xa), (Xa-1), (Xb), or(Xb-1), R¹² is -L¹-R¹³.

In some embodiments of a compound of Formula (X), (Xa), (Xa-1), (Xb), or(Xb-1), L¹ is —NH—. In some embodiments of a compound of Formula (X),(Xa), (Xa-1), (Xb), or (Xb-1), L¹ is —O— or —NH—.

In some embodiments of a compound of Formula (X), (Xa), (Xa-1), (Xb), or(Xb-1), R¹³ is C₁-C₆alkyl, C₁-C₆haloalkyl, or C₁-C₆deuteroalkyl.

In some embodiments of a compound of Formula (X), (Xa), (Xa-1), (Xb),(Xb-1), L⁵ is a saturated linear aliphatic chain having 1-8 carbon atomsoptionally substituted with one or more R^(L5), wherein 1, 2, or 3carbon atoms are optionally replaced with —NH—, —N(CH₃)—, —O—, —S—,—S(═O)—, —S(═O)₂—, or —-P(═O)—. In some embodiments of a compound ofFormula (X), (Xa), (Xa-1), (Xb), or (Xb-1), L⁵ is a saturated linearaliphatic chain having 1-8 carbon atoms optionally substituted with oneor more R^(L5), wherein 1, 2, or 3 carbon atoms are optionally replacedwith —NH—, —N(CH₃)—, or —O—. In some embodiments of a compound ofFormula (X), (Xa), (Xa-1), (Xb), or (Xb-1), L⁵ is a saturated linearaliphatic chain having 1-8 carbon atoms optionally substituted with oneor more R^(L5), wherein 1, 2, or 3 carbon atoms are optionally replacedwith —NH— or —O—.

In some embodiments of a compound of Formula (X), (Xa), (Xa-1), (Xb), or(Xb-1), L⁵ is a saturated linear aliphatic chain having 1-8 carbonatoms, wherein 1, 2, or 3 carbon atoms are optionally replaced with—NH—, —N(CH₃)—, —O—, —S—, —S(═O)—, or —S(═O)₂—. In some embodiments of acompound of Formula (X), (Xa), (Xa-1), (Xb), or (Xb-1), L⁵ is asaturated linear aliphatic chain having 1-8 carbon atoms, wherein 1, 2,or 3 carbon atoms are optionally replaced with —NH—, —N(CH₃)—, or —O—.In some embodiments of a compound of Formula (X), (Xa), (Xa-1), (Xb), or(Xb-1), L⁵ is a saturated linear aliphatic chain having 1-8 carbonatoms, wherein 1, 2, or 3 carbon atoms are optionally replaced with —NH—or —O—.

In some embodiments of a compound of Formula (X), (Xa), (Xa-1), (Xb), or(Xb-1), L⁵ is an unsaturated linear aliphatic chain having 1-8 carbonatoms optionally substituted with one or more R^(L5), wherein 1, 2, or 3carbon atoms are optionally replaced with —NH—, —N(CH₃)—, —O—, —S—,—S(═O)—, or —S(═O)₂—. In some embodiments of a compound of Formula (X),(Xa), (Xa-1), (Xb), or (Xb-1), L⁵ is an unsaturated linear aliphaticchain having 1-8 carbon atoms optionally substituted with one or moreR^(L5), wherein 1, 2, or 3 carbon atoms are optionally replaced with—NH—, —N(CH₃)—, or —O—. In some embodiments of a compound of Formula(X), (Xa), (Xa-1), (Xb), or (Xb-1), L⁵ is an unsaturated linearaliphatic chain having 1-8 carbon atoms optionally substituted with oneor more R^(L5), wherein 1, 2, or 3 carbon atoms are optionally replacedwith —NH— or —O—.

In some embodiments of a compound of Formula (X), (Xa), (Xa-1), (Xb), or(Xb-1), L⁵ is an unsaturated linear aliphatic chain having 1-8 carbonatoms, wherein 1, 2, or 3 carbon atoms are optionally replaced with—NH—, —N(CH₃)—, —O—, —S—, —S(═O)—, —S(═O)₂—, or —P(═O)—. In someembodiments of a compound of Formula (X), (Xa), (Xa-1), (Xb), or (Xb-1),L⁵ is an unsaturated linear aliphatic chain having 1-8 carbon atoms,wherein 1, 2, or 3 carbon atoms are optionally replaced with —NH—,—N(CH₃)—, or —O—. In some embodiments of a compound of Formula (X),(Xa), (Xa-1), (Xb), or (Xb-1), L⁵ is an unsaturated linear aliphaticchain having 1-8 carbon atoms, wherein 1, 2, or 3 carbon atoms areoptionally replaced with —NH— or —O—.

In some embodiments of a compound of Formula (X), (Xa), (Xa-1), (Xb), or(Xb-1), each R^(L5) is independently deuterium, halogen, —CN, —OR^(b),—NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆alkyl,C₁-C₆haloalkyl, or C₁-C₆deuteroalkyl. In some embodiments of a compoundof Formula (X), (Xa), (Xa-1), (Xb), or (Xb-1), each R^(L5) isindependently deuterium, halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, orC₁-C₆deuteroalkyl. In some embodiments of a compound of Formula (X),(Xa), (Xa-1), (Xb), or (Xb-1), each R^(L5) is independently deuterium orhalogen.

In some embodiments of a compound of Formula (X), (Xa), (Xa-1), (Xb), or(Xb-1), two R^(L5) on the same carbon atom are taken together to form anoxo.

In some embodiments of a compound of Formula (X), (Xa), (Xa-1), (Xb), or(Xb-1), L⁵ is

Also disclosed herein is a compound of Formula (XI), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof:

wherein:

-   -   L⁶ is a saturated or unsaturated linear aliphatic chain having        1-10 carbon atoms optionally substituted with one or more        R^(L6), wherein 1-5 carbon atoms are optionally replaced with        —NH—, —N(CH₃)—, —O—, —S—, —S(═O)—, —S(═O)₂—, or —P(═O)—;    -   each R^(L6) is independently deuterium, halogen, —CN, —OR^(b),        —SR^(b), —S(═O)R^(a), —S(═O)₂R^(a), —NO₂, —NR^(c)R^(d),        —NHS(═O)₂R^(a), —S(═O)₂NR^(c)R^(d), —C(═O)R^(a), —OC(═O)R^(a),        —C(═O)OR^(b), —OC(═O)OR^(b), —C(═O)NR^(c)R^(d),        —OC(═O)NR^(c)R^(d), —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a),        —NR^(b)C(═O)OR^(b), C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,        C₂-C₆alkenyl or C₂-C₆alkynyl;    -   or two R^(L6) on the same carbon atom are taken together to form        an oxo;    -   R³ is hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl, or        C₁-C₆deuteroalkyl;    -   R⁴ is hydrogen, deuterium, halogen, —CN, —OR^(b), —SR^(b),        —S(═O)R^(a), —S(═O)₂R^(a), —NO₂, —NR^(c)R^(d), —NHS(═O)₂R^(a),        —S(═O)₂NR^(c)R^(d), —C(═O)R^(a), —OC(═O)R^(a), —C(═O)OR^(b),        —OC(═O)OR^(b), —C(═O)NR^(c)R^(d), —OC(═O)NR^(c)R^(d),        —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a), —NR^(b)C(═O)OR^(b),        C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl,        C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₂-C₆alkenyl, or        C₂-C₆alkynyl;    -   or R³ and R⁴ are taken together to form an optionally        substituted ring;    -   L is a bond or —C(═O)—;    -   Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;        each optionally substituted with one or more R^(A);    -   each R^(A) is independently deuterium, halogen, —CN, —OR^(b),        —SR^(b), —S(═O)R^(a), —S(═O)₂R^(a), —NO₂, —NR^(c)R^(d),        —NHS(═O)₂R^(a), —S(═O)₂NR^(c)R^(d), —C(═O)R^(a), —OC(═O)R^(a),        —C(═O)OR^(b), —OC(═O)OR^(b), —C(═O)NR^(c)R^(d),        —OC(═O)NR^(c)R^(d), —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a),        —NR^(b)C(═O)OR^(b), C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,        C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl,        or heteroaryl; wherein each alkyl, alkenyl, alkenyl, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl is independently        optionally substituted with one or more oxo, deuterium, halogen,        —CN, —OR^(b), —NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b),        —C(═O)NR^(c)R^(d), C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   or two R^(A) on the same carbon are taken together to form an        oxo;    -   X is —CR^(x)— or —N—;    -   R^(x) is hydrogen, deuterium, halogen, —CN, —OR^(b), —SR^(b),        —S(═O)R^(a), —S(═O)₂R^(a), —NO₂, —NR^(c)R^(d), —NHS(═O)₂R^(a),        —S(═O)₂NR^(c)R^(d), —C(═O)R^(a), —OC(═O)R^(a), —C(═O)OR^(b),        —OC(═O)OR^(b), —C(═O)NR^(c)R^(d), —OC(═O)NR^(c)R^(d),        —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a), —NR^(b)C(═O)OR^(b),        C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl,        C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₂-C₆alkenyl, or        C₂-C₆alkynyl;    -   R⁵ is halogen, —CN, —OR⁸, —SR⁸, —S(═O)R⁷, —S(═O)₂R⁷, —NO₂,        —NHS(═O)₂R⁷, —S(═O)₂NR^(c)R^(d), —C(═O)R⁷, —OC(═O)R⁷, —C(═O)OR⁸,        —OC(═O)OR⁸, —C(═O)NR⁹R¹⁰, —OC(═O)NR⁹R¹⁰, —NR⁸C(═O)NR⁹R¹⁰,        —NR⁸C(═O)R⁷, —NR⁸C(═O)OR⁸, C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,        C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl,        or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl is independently        optionally substituted with one or more oxo, deuterium, halogen,        —CN, —OR^(b), —NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b),        —C(═O)NR^(c)R^(d), C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   or R^(x) and R⁵ are taken together to form ring D optionally        substituted with one or more R^(D);    -   Ring D is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;    -   each R^(D) is independently hydrogen, deuterium, halogen, —CN,        —OR^(b), —SR^(b), —S(═O)R^(a), —S(═O)₂R^(a), —NO₂, —NR^(c)R^(d),        —NHS(═O)₂R^(a), —S(═O)₂NR^(c)R^(d), —C(═O)R^(a), —OC(═O)R^(a),        —C(═O)OR^(b), —OC(═O)OR^(b), —C(═O)NR^(c)R^(d),        —OC(═O)NR^(c)R^(d), —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a),        —NR^(b)C(═O)OR^(b), C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,        C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl,        or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl is independently        optionally substituted with one or more oxo, deuterium, halogen,        —CN, —OR^(b), —NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b),        —C(═O)NR^(c)R^(d), C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   or two R^(D) on the same carbon are taken together to form an        oxo;    -   R⁷ is C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl,        C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,        cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each        alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one or        more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH₂, —C(═O)Me,        —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   each R⁸ is independently hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,        C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl,        or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl is independently        optionally substituted with one or more oxo, deuterium, halogen,        —CN, —OH, —OMe, —NH₂, —C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl,        or C₁-C₆haloalkyl;    -   R⁹ and R¹⁰ are independently hydrogen, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,        C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl,        alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one or        more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH₂, —C(═O)Me,        —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   or R⁹ and R¹⁰ are taken together with the nitrogen atom to which        they are attached to form a heterocycloalkyl optionally        substituted with one or more oxo, deuterium, halogen, —CN, —OH,        —OMe, —NH₂, —C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or        C₁-C₆haloalkyl;    -   each R^(a) is independently C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,        C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl,        or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl is independently        optionally substituted with one or more oxo, deuterium, halogen,        —CN, —OH, —OMe, —NH₂, —C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl,        or C₁-C₆haloalkyl;    -   each R^(b) is independently hydrogen, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,        C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl,        alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one or        more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH₂, —C(═O)Me,        —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   each R^(c) and R^(d) is independently hydrogen, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,        C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl,        alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one or        more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH₂, —C(═O)Me,        —C(═O)OH, —C(—O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   or R^(c) and R^(d) are taken together with the nitrogen atom to        which they are attached to form a heterocycloalkyl optionally        substituted with one or more oxo, deuterium, halogen, —CN, —OH,        —OMe, —NH₂, —C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or        C₁-C₆haloalkyl.

In some embodiments of a compound of Formula (XI), L is a bond. In someembodiments of a compound of Formula (XI), L is —C(═O)—.

In some embodiments of a compound of Formula (XI), Ring A isheterocycloalkyl or heteroaryl; each optionally substituted with one ormore R^(A). In some embodiments of a compound of Formula (XI), Ring A isa 5-membered heterocycloalkyl or a 5-membered heteroaryl; eachoptionally substituted with one or more R^(A). In some embodiments of acompound of Formula (XI), Ring A is heteroaryl optionally substitutedwith one or more R^(A).

In some embodiments of a compound of Formula (XI), each R^(A) isindependently deuterium, halogen, —CN, —OR^(b), —NR^(c)R^(d),—C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d), —OC(═O)NR^(c)R^(d),C₁-C₆alkyl, C₁-C₆haloalkyl, or C₁-C₆deuteroalkyl. In some embodiments ofa compound of Formula (XI), each R^(A) is independently deuterium,halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, or C₁-C₆deuteroalkyl. In someembodiments of a compound of Formula (XI), each R^(A) is independentlyhalogen or C₁-C₆alkyl. In some embodiments of a compound of Formula(XI), each R^(A) is independently C₁-C₆alkyl.

In some embodiments of a compound of Formula (XI), R⁴ is hydrogen,deuterium, halogen, —CN, —OR^(b), NR^(c)R^(d), —C(═O)R^(a),—C(═O)OR^(b), —C(═O)NR^(c)R^(d), —OC(═O)NR^(c)R^(d), C₁-C₆alkyl,C₁-C₆haloalkyl, or C₁-C₆deuteroalkyl. In some embodiments of a compoundof Formula (XI), R⁴ is hydrogen or —OR^(b). In some embodiments of acompound of Formula (XI), R⁴ is —OR^(b). In some embodiments of acompound of Formula (XI), R⁴ is hydrogen.

In some embodiments of a compound of Formula (XI), X is —CH—. In someembodiments of a compound of Formula (IX), X is —N—.

In some embodiments of a compound of Formula (XI), the compound is ofFormula (XIa):

In some embodiments of a compound of Formula (XI), the compound is ofFormula (XIb):

In some embodiments of a compound of Formula (XI), (XIa), or (XIb), R³is hydrogen or C₁-C₆alkyl. In some embodiments of a compound of Formula(XI), (XIa), or (XIb), R³ is hydrogen.

In some embodiments of a compound of Formula (XI), (XIa), or (XIb), R⁵is halogen, —CN, —OR⁸, —NR⁹R¹⁰, —C(═O)R⁷, —C(═O)OR⁸, —C(═O)NRR¹⁰,—NR⁸C(═O)NR⁹R¹⁰, —NR⁸C(═O)R⁷, —NR⁸C(═O)OR⁸, C₁-C₆alkyl, C₁-C₆haloalkyl,C₁-C₆deuteroalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl,heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is independently optionallysubstituted with one or more oxo, deuterium, halogen, —CN, —OR^(b),—NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆alkyl,or C₁-C₆haloalkyl.

In some embodiments of a compound of Formula (XI), (XIa), or (XIb), R⁵is —OR⁸, —NR⁹R¹⁰, —C(═O)R⁷, —C(═O)OR⁸, —C(═O)NR⁹R¹⁰, —NR⁸C(═O)NR⁹R¹⁰,—NR⁸C(═O)R⁷, —NR⁸C(═O)OR⁸, cycloalkyl, heterocycloalkyl, aryl, orheteroaryl; wherein each cycloalkyl, heterocycloalkyl, aryl, andheteroaryl is independently optionally substituted with one or more oxo,deuterium, halogen, —CN, —OR^(b), —NR^(c)R^(d), —C(═O)R^(a),—C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆alkyl, or C₁-C₆haloalkyl.

In some embodiments of a compound of Formula (XI), (XIa), or (XIb), R⁵is —OR⁸, —NR⁹R¹⁰, —NR⁸C(═O)R⁷, or aryl optionally substituted with oneor more oxo, deuterium, halogen, —CN, —OR^(b), —NR^(c)R^(d),—C(═O)R^(a), —C(═O)OR⁸, —C(═O)NR^(c)R^(d), C₁-C₆alkyl, orC₁-C₆haloalkyl.

In some embodiments of a compound of Formula (XI), (XIa), or (XIb), R⁵is —OR⁸, —NR⁹R¹⁰, —NR⁸C(═O)R⁷, cycloalkyl, heterocycloalkyl, aryl, orheteroaryl; wherein each cycloalkyl, heterocycloalkyl, aryl, andheteroaryl is independently optionally substituted with one or more oxo,deuterium, halogen, —CN, —OR^(b), —NR^(c)R^(d), —C(═O)R^(a),—C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆alkyl, or C₁-C₆haloalkyl. In someembodiments of a compound of Formula (XI), (XIa), or (XIb), R⁵ is—NR⁸C(═O)R⁷. In some embodiments of a compound of Formula (XI), (XIa),or (XIb), R⁵ is aryl optionally substituted with one or more oxo,deuterium, halogen, —CN, —OR^(b), —NR^(c)R^(d), —C(═O)R^(a),—C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆alkyl, or C₁-C₆haloalkyl.

In some embodiments of a compound of Formula (XI), (XIa), or (XIb), R⁷is C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, cycloalkyl,heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is independently optionallysubstituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe,—NH₂, —C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl. Insome embodiments of a compound of Formula (XI), (XIa), or (XIb), R⁷ isC₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, or cycloalkyl; whereineach alkyl, cycloalkyl, and heterocycloalkyl is independently optionallysubstituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe,—NH₂, —C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl. Insome embodiments of a compound of Formula (XI), (XIa), or (XIb), R⁷ iscycloalkyl optionally substituted with one or more oxo, deuterium,halogen, —CN, —OH, —OMe, —NH₂, —C(═O)Me, —C(═O)OH, —C(═O)OMe,C₁-C₆alkyl, or C₁-C₆haloalkyl. In some embodiments of a compound ofFormula (XI), (XIa), or (XIb), R⁷ is unsubstituted cycloalkyl.

In some embodiments of a compound of Formula (XI), (XIa), or (XIb), R⁸is hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, cycloalkyl,heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is independently optionallysubstituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe,—C(═O)Me, —C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl. In some embodimentsof a compound of Formula (XI), (XIa), or (XIb), R⁸ is hydrogen,C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, or cycloalkyl; whereineach alkyl, cycloalkyl, and heterocycloalkyl is independently optionallysubstituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe,—NH₂, —C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl.

In some embodiments of a compound of Formula (XI), (XIa), or (XIb), R⁹and R¹⁰ are independently hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl,C₁-C₆deuteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroarylis independently optionally substituted with one or more oxo, deuterium,halogen, —CN, —OH, —OMe, —C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, orC₁-C₆haloalkyl. In some embodiments of a compound of Formula (XI),(XIa), or (XIb), R⁹ and R¹⁰ are independently hydrogen, C₁-C₆alkyl,C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, or cycloalkyl; wherein each alkyl,cycloalkyl, and heterocycloalkyl is independently optionally substitutedwith one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH₂,—C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl.

In some embodiments of a compound of Formula (XI), (XIa), or (XIb), L⁶is a saturated linear aliphatic chain having 1-8 carbon atoms optionallysubstituted. with one or more R^(L6), wherein 1, 2, or 3 carbon atomsare optionally replaced with —NH—, —N(CH₃)—, —O—, —S—, —S(═O)—, or—S(═O)₂—. In some embodiments of a compound of Formula (XI), (XIa), or(XIb), L⁶ is a saturated linear aliphatic chain having 1-8 carbon atomsoptionally substituted with one or more R^(L6), wherein 1, 2, or 3carbon atoms are optionally replaced with —NH—, —N(CH₃)—, or —O—. Insome embodiments of a compound of Formula (XI), (XIa), or (XIb), L⁶ is asaturated linear aliphatic chain having 1-8 carbon atoms optionallysubstituted with one or more R^(L6), wherein 1, 2, or 3 carbon atoms areoptionally replaced with -—NH— or —O—.

In some embodiments of a compound of Formula (XI), (XIa), or (XIb), L⁶is a saturated linear aliphatic chain having 1-8 carbon atoms, wherein1, 2, or 3 carbon atoms are optionally replaced with —NH—, —N(CH₃)—,—O—, —S—, —S(═O)—, or —S(═O)₂—. In some embodiments of a compound ofFormula (XI), (XIa), or (XIb), L⁶ is a saturated linear aliphatic chainhaving 1-8 carbon atoms, wherein 1, 2, or 3 carbon atoms are optionallyreplaced with —NH—, —N(CH₃)—, or —O—. In some embodiments of a compoundof Formula (XI), (XIa), or (XIb), L⁶ is a saturated linear aliphaticchain having 1-8 carbon atoms, wherein 1, 2, or 3 carbon atoms areoptionally replaced with —NH— or —O—.

In some embodiments of a compound of Formula (XI), (XIa), or (XIb), L⁶is an unsaturated linear aliphatic chain having 1-8 carbon atomsoptionally substituted with one or more R^(L6), wherein 1, 2, or 3carbon atoms are optionally replaced with —NH—, —N(CH₃)—, —O—, —S—,—S(═O)—, or —S(═O)₂—, or —P(═O)—. In some embodiments of a compound ofFormula (XI), (XIa), or (XIb), L⁶ is an unsaturated linear aliphaticchain having 1-8 carbon atoms optionally substituted with one or moreR^(L6), wherein 1, 2, or 3 carbon atoms are optionally replaced with—NH—, —N(CH₃)—, or —O—. In some embodiments of a compound of Formula(XI), (XIa), or (XIb), L⁶ is an unsaturated linear aliphatic chainhaving 1-8 carbon atoms optionally substituted with one or more R^(L6),wherein 1, 2, or 3 carbon atoms are optionally replaced with —NH— or—O—.

In some embodiments of a compound of Formula (XI), (XIa), or (XIb), L⁶is an unsaturated linear aliphatic chain having 1-S carbon atoms,wherein 1, 2, or 3 carbon atoms are optionally replaced with —NH—,—N(CH₃)—, —O—, —S—, —S(═O)—, or —S(═O)₂—, or —P(═O)—. In someembodiments of a compound of Formula (XI), (XIa), or (XIb), L⁶ is anunsaturated linear aliphatic chain having 1-8 carbon atoms, wherein 1,2, or 3 carbon atoms are optionally replaced with —NH—, —N(CH₃)—, or—O—. In some embodiments of a compound of Formula (XI), (XIa), or (XIb),L⁶ is an unsaturated linear aliphatic chain having 1-8 carbon atoms,wherein 1, 2, or 3 carbon atoms are optionally replaced with —NH— or—O—.

In some embodiments of a compound of Formula (XI), (XIa), or (XIb), eachR^(L6) is independently deuterium, halogen, —CN, —OR^(b), —NR^(c)R^(d),—C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆alkyl,C₁-C₆haloalkyl, or C₁-C₆deuteroalkyl. In some embodiments of a compoundof Formula (XI), (XIa), or (XIb), each R^(L6) is independentlydeuterium, halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, or C₁-C₆deuteroalkyl. Insome embodiments of a compound of Formula (XI), (XIa), or (XIb), eachR^(L6) is independently deuterium or halogen.

In some embodiments of a compound of Formula (XI), (XIa), or (XIb), twoR^(L6) on the same carbon atom are taken together to form an oxo.

In some embodiments of a compound of Formula (XI), (XIa), or (XIb), L⁶is

Also disclosed herein is a compound of Formula (XII), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof:

wherein:

-   -   Ring B is cycloalkyl, heterocycloalkyl, aryl, heteroaryl;    -   R¹⁶ is —C(═O)NR¹R², —C(═N—CN)NR¹R², —P(═O)R¹R², or —C(═O)R¹¹;    -   R¹ and R² are independently hydrogen, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,        C₁-C₆aminoalkyl, C₂-C₆alkenyl, or C₂-C₆alkynyl;    -   R³ is hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl, or        C₁-C₆deuteroalkyl;    -   R⁴ is hydrogen, deuterium, halogen, —CN, —OR^(b), —SR^(b),        —S(═O)R^(a), —S(═O)₂R^(a), —NO₂, —NR^(c)R^(d), —NHS(═O)₂R^(a),        —S(═O)₂NR^(c)R^(d), —C(═O)R^(a), —OC(═O)R^(a), —C(═O)OR^(b),        —OC(═O)OR^(b), —C(═O)NR^(c)R^(d), —OC(═O)NR^(c)R^(d),        —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a), —NR^(b)C(═O)OR^(b),        C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl,        C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₂-C₆alkenyl, or        C₂-C₆alkynyl;    -   or R³ and R⁴ are taken together to form an optionally        substituted ring;    -   L is a bond or —C(═O)—;    -   Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;        each optionally substituted with one or more R^(A);    -   each R^(A) is independently deuterium, halogen, —CN, —OR^(b),        —SR^(b), —S(═O)R^(a), —S(═O)₂R^(a), —NO₂, —NR^(c)R^(d),        —NHS(═O)₂R^(a), —S(═O)₂NR^(c)R^(d), —C(═O)R^(a), —OC(═O)R^(a),        —C(═O)OR^(b), —OC(═O)OR^(b), —C(═O)NR^(c)R^(d),        —OC(═O)NR^(c)R^(d), —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a),        —NR^(b)C(═O)OR^(b), C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,        C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl,        or heteroaryl; wherein each alkyl, alkenyl, alkenyl, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl is independently        optionally substituted with one or more oxo, deuterium, halogen,        —CN, —OR^(b), —NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b),        —C(═O)NR^(c)R^(d), C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   or two R^(A) on the same carbon are taken together to form an        oxo;    -   or -L-Ring A is absent;    -   X is independently —CR^(x)— or —N—;    -   each R^(x) is independently hydrogen, deuterium, halogen, —CN,        —OR^(b), —SR^(b), —S(═O)R^(a), —S(═O)₂R^(a), —NO₂, —NR^(c)R^(d),        —NHS(═O)₂R^(a), —S(═O)₂NR^(c)R^(d), —C(═O)R^(a), —OC(═O)R^(a),        —C(═O)OR^(b), —OC(═O)OR^(b), —C(═O)NR^(c)R^(d),        —OC(═O)NR^(c)R^(d), —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a),        —NR^(b)C(═O)OR^(b), C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,        C₂-C₆alkenyl, or C₂-C₆alkynyl;    -   R⁵ is halogen, —CN, —OR⁸, —SR⁸, —S(═O)R⁷, —S(═O)₂R⁷, —NO₂,        —NR⁹R¹⁰, —NR⁸S(═O)R⁷, —NR⁸S(═O)₂R⁷, —S(═O)₂NR⁹R¹⁰, —C(═N—CN)R⁷,        —C(═O)R⁷, 13 OC(═N—CN)R⁷, —OC(—O)R⁷, —C(═N—CN)OR⁸, —C(═O)OR⁸,        —OC(═N—CN)OR⁸, —OC(═O)OR⁸, —C(═N—CN)NR⁹R¹⁰, —C(═O)NR⁹R¹⁰,        —OC(═N—CN)NR⁹R¹⁰, —OC(═O)NR⁹R¹⁰, —NR⁸C(═N—CN)NR⁹R¹⁰,        —NR⁸C(═O)NR⁹R¹⁰, —NR⁸C(═N—CN)R⁷, —NR⁸C(═N—OH)R⁷,        —NR⁸C(═N—CN)OR⁸, —NR⁸C(═O)OR⁸, —NR⁸S(═O)(═NR⁸)R⁷, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,        C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl is independently        optionally substituted with one or more oxo, deuterium, halogen,        —CN, —OR^(b), —NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b),        —C(═O)NR^(c)R^(d), C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,        C₁-C₆heteroalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl,        heterocycloalkyl, aryl, heteroaryl, C₁-C₆alkyl(cycloalkyl),        C₁-C₆alkyl(heterocycloalkyl), C₁-C₆alkyl(aryl), or        C₁-C₆alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl,        cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is        independently optionally substituted with one or more oxo,        deuterium, halogen, —CN, —OR^(b), —NR^(c)R^(d), —C(═O)R^(a),        —C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   or R^(x) and R⁵ are taken together to form ring D optionally        substituted with one or more R^(D);    -   Ring D is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;    -   each R^(D) is independently hydrogen, deuterium, halogen, —CN,        —OR^(b), —SR^(b), —S(═O)R^(a), —S(═O)₂R^(a), —NO₂, —NR^(c)R^(d),        —NHS(═O)₂R^(a), —S(═O)₂NR^(c)R^(d), —C(═O)R^(a), —OC(═O)R^(a),        —C(═O)OR^(b), —OC(═O)OR^(b), —C(═O)NR^(c)R^(d),        —OC(═O)NR^(c)R^(d), —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a),        —NR^(b)C(═O)OR^(b), C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,        C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl,        or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl is independently        optionally substituted with one or more oxo, deuterium, halogen,        —CN, —OR^(b), —NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b),        —C(═O)NR^(c)R^(d), C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   or two R^(D) on the same carbon are taken together to form an        oxo;    -   R⁷ is C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl,        C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,        cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each        alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one or        more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH₂, —C(═O)Me,        —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   each R⁸ is independently hydrogen, CN, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,        C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl,        alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one or        more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH₂, —C(═O)Me,        —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   R⁹ and R¹⁰ are independently hydrogen, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,        C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl,        alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one or        more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH₂, —C(═O)Me,        —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, C₁-C₆deuteroalkyl,        C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆hydroxydeuteroalkyl,        cycloalkyl, or heterocycloalkyl;    -   or R⁹ and R¹⁰ are taken together with the nitrogen atom to which        they are attached to form a heterocycloalkyl optionally        substituted with one or more oxo, deuterium, halogen, —CN, —OH,        —OMe, —NH₂, —C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or        C₁-C₆haloalkyl;    -   or R⁸ and R⁹ are taken together with the atoms to which they are        attached to form a heterocycloalkyl optionally substituted with        one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH₂,        —C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   R¹¹ is C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl,        C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,        cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each        alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one or        more R^(11a);    -   each R^(11a) is independently deuterium, halogen, —CN, —OR^(b),        —SR^(b), —S(═O)R^(a), —S(═O)₂R^(a), —NO₂, —NR^(c)R^(d),        —NHS(═O)₂R^(a), —S(═O)₂NR^(c)R^(d), —C(═O)R^(a), —OC(═O)R^(a),        —C(═O)OR^(b), —OC(═O)OR^(b), —C(═O)NR^(c)R^(d),        —OC(═O)NR^(c)R^(d), —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a),        —NR^(b)C(═O)OR^(b), C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,        C₂-C₆alkenyl, or C₂-C₆alkenyl;    -   each R^(a) is independently C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,        C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl,        or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl is independently        optionally substituted with one or more oxo, deuterium, halogen,        —CN, —OH, —OMe, —NH₂, —C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl,        or C₁-C₆haloalkyl;    -   each R^(b) is independently hydrogen, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,        C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl,        alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one or        more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH₂, —C(═O)Me,        —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   each R^(c) and R^(d) is independently hydrogen, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,        C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl,        alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one or        more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH₂, —C(═O)Me,        —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   or R^(c) and R^(d) are taken together with the nitrogen atom to        which they are attached to form a heterocycloalkyl optionally        substituted with one or more oxo, deuterium, halogen, —CN, —OH,        —OMe, —NH₂, —C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or        C₁-C₆haloalkyl.

Also disclosed herein is a compound of Formula (XII), or apharmaceutically acceptable salt, stereoisomer, or solvate thereof:

wherein:

-   -   Ring B is cycloalkyl, heterocycloalkyl, aryl, heteroaryl;    -   R¹⁶ is —C(═O)NR¹R², —C(═N—CN)NR¹R², —P(═O)R¹R², or —C(═O)R¹¹;    -   R¹ and R² are independently hydrogen, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,        C₁-C₆aminoalkyl, C₂-C₆alkenyl, or C₂-C₆alkynyl;    -   R³ is hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl, or        C₁-C₆deuteroalkyl;    -   R⁴ is hydrogen, deuterium, halogen, —CN, —OR^(b), —SR^(b),        —S(═O)R^(a), —S(═O)₂R^(a), —NO₂, —NR^(c)R^(d), —NHS(═O)₂R^(a),        —S(═O)₂NR^(c)R^(d), —C(═O)R^(a), —OC(═O)R^(a), —C(═O)OR^(b),        —OC(═O)OR^(b), —C(═O)NR^(c)R^(d), —OC(═O)NR^(c)R^(d),        —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a), —NR^(b)C(═O)OR^(b),        C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl,        C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₂-C₆alkenyl, or        C₂-C₆alkynyl;    -   or R³ and R⁴ are taken together to form an optionally        substituted ring;    -   L is a bond or —C(═O)—;    -   Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;        each optionally substituted with one or more R^(A);    -   each R^(A) is independently deuterium, halogen, —CN, —OR^(b),        —SR^(b), —S(═O)R^(a), —S(═O)₂R^(a), —NO₂, —NR^(c)R^(d),        —NHS(═O)₂R^(a), —S(═O)₂NR^(c)R^(d), —C(═O)R^(a), —OC(═O)R^(a),        —C(═O)OR^(b), —OC(═O)OR^(b), —C(═O)NR^(c)R^(d),        —OC(═O)NR^(c)R^(d), —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a),        —NR^(b)C(═O)OR^(b), C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,        C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl,        or heteroaryl; wherein each alkyl, alkenyl, alkenyl, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl is independently        optionally substituted with one or more oxo, deuterium, halogen,        —CN, —OR^(b), —NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b),        —C(═O)NR^(c)R^(d), C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   or two R^(A) on the same carbon are taken together to form an        oxo;    -   or -L-Ring A is absent;    -   each X is independently —CR^(x)— or —N—;    -   each R^(x) is independently hydrogen, deuterium, halogen, —CN,        —OR^(b), —SR^(b), —S(═O)R^(a), —S(═O)₂R^(a), —NO₂, —NR^(c)R^(d),        —NHS(═O)₂R^(a), —S(═O)₂NR^(c)R^(d), —C(═O)R^(a), —OC(═O)R^(a),        —C(═O)OR^(b), —OC(═O)OR^(b), —C(═O)NR^(c)R^(d),        —OC(═O)NR^(c)R^(d), —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a),        —NR^(b)C(═O)OR^(b), C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,        C₂-C₆alkenyl, or C₂-C₆alkynyl;    -   R⁵ is halogen, —CN, —OR⁸, —SR⁸, —S(═O)R⁷, —S(═O)₂R⁷, —NO₂,        —NR⁹R¹⁰, —NR⁸S(═O)R⁷, —NR⁸S(═O)₂R⁷, —S(═O)₂NR⁹R¹⁰, —C(═N—CN)R⁷,        —C(═O)R⁷, 13 OC(═N—CN)R⁷, —OC(—O)R⁷, —C(═N—CN)OR⁸, —C(═O)OR⁸,        —OC(═N—CN)OR⁸, —OC(═O)OR⁸, —C(═N—CN)NR⁹R¹⁰, —C(═O)NR⁹R¹⁰,        —OC(═N—CN)NR⁹R¹⁰, —OC(═O)NR⁹R¹⁰, —NR⁸C(═N—CN)NR⁹R¹⁰,        —NR⁸C(═O)NR⁹R¹⁰, —NR⁸C(═N—CN)R⁷, —NR⁸C(═N—OH)R⁷,        —NR⁸C(═N—CN)OR⁸, —NR⁸C(═O)OR⁸, —NR⁸S(═O)(═NR⁸)R⁷, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,        C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl; wherein each alkyl,        alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one or        more oxo, deuterium, halogen, —CN, —OR^(b), —NR^(c)R^(d),        —C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,        C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,        cycloalkyl, heterocycloalkyl, aryl, heteroaryl,        C₁-C₆alkyl(cycloalkyl), C₁-C₆alkyl(heterocycloalkyl),        C₁-C₆alkyl(aryl), or C₁-C₆alkyl(heteroaryl); wherein each alkyl,        alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one or        more oxo, deuterium, halogen, —CN, —OR^(b), —NR^(c)R^(d),        —C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆alkyl, or        C₁-C₆haloalkyl;    -   R⁷ is C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl,        C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,        cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each        alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one or        more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH₂, —C(═O)Me,        —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   each R⁸ is independently hydrogen, CN, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,        C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl,        alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one or        more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH₂, —C(═O)Me,        —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   R⁹ and R¹⁰ are independently hydrogen, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,        C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl,        alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one or        more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH₂, —C(═O)Me,        —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, C₁-C₆deuteroalkyl,        C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆hydroxydeuteroalkyl,        cycloalkyl, or heterocycloalkyl;    -   or R⁹ and R¹⁰ are taken together with the nitrogen atom to which        they are attached to form a heterocycloalkyl optionally        substituted with one or more oxo, deuterium, halogen, —CN, —OH,        —OMe, —NH₂, —C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or        C₁-C₆haloalkyl;    -   or R⁸ and R⁹ are taken together with the atoms to which they are        attached to form a heterocycloalkyl optionally substituted with        one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH₂,        —C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   R¹¹ is C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl,        C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,        cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each        alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one or        more R^(11a);    -   each R^(11a) is independently deuterium, halogen, —CN, —OR^(b),        —SR^(b), —S(═O)R^(a), —S(═O)₂R^(a), —NO₂, —NR^(c)R^(d),        —NHS(═O)₂R^(a), —S(═O)₂NR^(c)R^(d), —C(═O)R^(a), —OC(═O)R^(a),        —C(═O)OR^(b), —OC(═O)OR^(b), —C(═O)NR^(c)R^(d),        —OC(═O)NR^(c)R^(d), —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a),        —NR^(b)C(═O)OR^(b), C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,        C₂-C₆alkenyl, or C₂-C₆alkenyl;    -   each R^(a) is independently C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,        C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl,        or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl is independently        optionally substituted with one or more oxo, deuterium, halogen,        —CN, —OH, —OMe, —NH₂, —C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl,        or C₁-C₆haloalkyl;    -   each R^(b) is independently hydrogen, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,        C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl,        alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one or        more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH₂, —C(═O)Me,        —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   each R^(c) and R^(d) is independently hydrogen, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,        C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl,        alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one or        more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH₂, —C(═O)Me,        —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   or R^(c) and R^(d) are taken together with the nitrogen atom to        which they are attached to form a heterocycloalkyl optionally        substituted with one or more oxo, deuterium, halogen, —CN, —OH,        —OMe, —NH₂, —C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or        C₁-C₆haloalkyl.

Also disclosed herein is a compound of Formula (XII), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof:

wherein:

-   -   Ring B is cycloalkyl, heterocycloalkyl, aryl, heteroaryl;    -   R¹⁶ is —C(═O)NR¹R², —C(═N—CN)NR¹R², —P(═O)R¹R², or —C(═O)R¹¹;    -   R¹ and R² are independently hydrogen, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,        C₁-C₆aminoalkyl, C₂-C₆alkenyl, or C₂-C₆alkynyl;    -   R³ is hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl, or        C₁-C₆deuteroalkyl;    -   R⁴ is hydrogen, deuterium, halogen, —CN, —OR^(b), —SR^(b),        —S(═O)R^(a), —S(═O)₂R^(a), —NO₂, —NR^(c)R^(d), —NHS(═O)₂R^(a),        —S(═O)₂NR^(c)R^(d), —C(═O)R^(a), —OC(═O)R^(a), —C(═O)OR^(b),        —OC(═O)OR^(b), —C(═O)NR^(c)R^(d), —OC(═O)NR^(c)R^(d),        —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a), —NR^(b)C(═O)OR^(b),        C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl,        C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₂-C₆alkenyl, or        C₂-C₆alkynyl;    -   or R³ and R⁴ are taken together to form an optionally        substituted ring;    -   L is a bond or —C(═O)—;    -   Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;        each optionally substituted with one or more R^(A);    -   each R^(A) is independently deuterium, halogen, —CN, —OR^(b),        —SR^(b), —S(═O)R^(a), —S(═O)₂R^(a), —NO₂, —NR^(c)R^(d),        —NHS(═O)₂R^(a), —S(═O)₂NR^(c)R^(d), —C(═O)R^(a), —OC(═O)R^(a),        —C(═O)OR^(b), —OC(═O)OR^(b), —C(═O)NR^(c)R^(d),        —OC(═O)NR^(c)R^(d), —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a),        —NR^(b)C(═O)OR^(b), C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,        C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl,        or heteroaryl; wherein each alkyl, alkenyl, alkenyl, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl is independently        optionally substituted with one or more oxo, deuterium, halogen,        —CN, —OR^(b), —NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b),        —C(═O)NR^(c)R^(d), C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   or two R^(A) on the same carbon are taken together to form an        oxo;    -   each X is independently —CR^(x)— or —N—;    -   each R^(x) is independently hydrogen, deuterium, halogen, —CN,        —OR^(b), —SR^(b), —S(═O)R^(a), —S(═O)₂R^(a), —NO₂, —NR^(c)R^(d),        —NHS(═O)₂R^(a), —S(═O)₂NR^(c)R^(d), —C(═O)R^(a), —OC(═O)R^(a),        —C(═O)OR^(b), —OC(═O)OR^(b), —C(═O)NR^(c)R^(d),        —OC(═O)NR^(c)R^(d), —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a),        —NR^(b)C(═O)OR^(b), C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,        C₂-C₆alkenyl, or C₂-C₆alkynyl;    -   R⁵ is halogen, —CN, —OR⁸, —SR⁸, —S(═O)R⁷, —S(═O)₂R⁷, —NO₂,        —NR⁹R¹⁰, —NR⁸S(═O)R⁷, —NR⁸S(═O)₂R⁷, —S(═O)₂NR⁹R¹⁰, —C(═N—CN)R⁷,        —C(═O)R⁷, 13 OC(═N—CN)R⁷, —OC(—O)R⁷, —C(═N—CN)OR⁸, —C(═O)OR⁸,        —OC(═N—CN)OR⁸, —OC(═O)OR⁸, —C(═N—CN)NR⁹R¹⁰, —C(═O)NR⁹R¹⁰,        —OC(═N—CN)NR⁹R¹⁰, —OC(═O)NR⁹R¹⁰, —NR⁸C(═N—CN)NR⁹R¹⁰,        —NR⁸C(═O)NR⁹R¹⁰, —NR⁸C(═N—CN)R⁷, —NR⁸C(═N—OH)R⁷,        —NR⁸C(═N—CN)OR⁸, —NR⁸C(═O)OR⁸, —NR⁸S(═O)(═NR⁸)R⁷, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,        C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl,        alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one or        more oxo, deuterium, halogen, —CN, —OR^(b), —NR^(c)R^(d),        —C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,        C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,        cycloalkyl, heterocycloalkyl, aryl, heteroaryl,        C₁-C₆alkyl(cycloalkyl), C₁-C₆alkyl(heterocycloalkyl),        C₁-C₆alkyl(aryl), or C₁-C₆alkyl(heteroaryl); wherein each alkyl,        alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one or        more oxo, deuterium, halogen, —CN, —OR^(b), —NR^(c)R^(d),        —C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆alkyl, or        C₁-C₆haloalkyl;    -   or R^(x) and R⁵ are taken together to form ring D optionally        substituted with one or more R^(D);    -   Ring D is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;    -   each R^(D) is independently hydrogen, deuterium, halogen, —CN,        —OR^(b), —SR^(b), —S(═O)R^(a), —S(═O)₂R^(a), —NO₂, —NR^(c)R^(d),        —NHS(═O)₂R^(a), —S(═O)₂NR^(c)R^(d), —C(═O)R^(a), —OC(═O)R^(a),        —C(═O)OR^(b), —OC(═O)OR^(b), —C(═O)NR^(c)R^(d),        —OC(═O)NR^(c)R^(d), —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a),        —NR^(b)C(═O)OR^(b), C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,        C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl,        or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl is independently        optionally substituted with one or more oxo, deuterium, halogen,        —CN, —OR^(b), —NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b),        —C(═O)NR^(c)R^(d), C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   or two R^(D) on the same carbon are taken together to form an        oxo;    -   R⁷ is C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl,        C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,        cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each        alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one or        more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH₂, —C(═O)Me,        —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   each R⁸ is independently hydrogen, CN, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,        C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl,        alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one or        more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH₂, —C(═O)Me,        —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   R⁹ and R¹⁰ are independently hydrogen, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,        C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl,        alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one or        more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH₂, —C(═O)Me,        —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, C₁-C₆deuteroalkyl,        C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆hydroxydeuteroalkyl,        cycloalkyl, or heterocycloalkyl;    -   or R⁹ and R¹⁰ are taken together with the nitrogen atom to which        they are attached to form a heterocycloalkyl optionally        substituted with one or more oxo, deuterium, halogen, —CN, —OH,        —OMe, —NH₂, —C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or        C₁-C₆haloalkyl;    -   or R⁸ and R⁹ are taken together with the atoms to which they are        attached to form a heterocycloalkyl optionally substituted with        one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH₂,        —C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   R¹¹ is C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl,        C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,        cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each        alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one or        more R^(11a);    -   each R^(11a) is independently deuterium, halogen, —CN, —OR^(b),        —SR^(b), —S(═O)R^(a), —S(═O)₂R^(a), —NO₂, —NR^(c)R^(d),        —NHS(═O)₂R^(a), —S(═O)₂NR^(c)R^(d), —C(═O)R^(a), —OC(═O)R^(a),        —C(═O)OR^(b), —OC(═O)OR^(b), —C(═O)NR^(c)R^(d),        —OC(═O)NR^(c)R^(d), —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a),        —NR^(b)C(═O)OR^(b), C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,        C₂-C₆alkenyl, or C₂-C₆alkenyl;    -   each R^(a) is independently C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,        C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl,        or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl is independently        optionally substituted with one or more oxo, deuterium, halogen,        —CN, —OH, —OMe, —NH₂, —C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl,        or C₁-C₆haloalkyl;    -   each R^(b) is independently hydrogen, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,        C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl,        alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one or        more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH₂, —C(═O)Me,        —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   each R^(c) and R^(d) is independently hydrogen, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,        C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl,        alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one or        more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH₂, —C(═O)Me,        —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   or R^(c) and R^(d) are taken together with the nitrogen atom to        which they are attached to form a heterocycloalkyl optionally        substituted with one or more oxo, deuterium, halogen, —CN, —OH,        —OMe, —NH₂, —C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or        C₁-C₆haloalkyl.

Also disclosed herein is a compound of Formula (XII), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof:

wherein:

-   -   Ring B is cycloalkyl, heterocycloalkyl, aryl, heteroaryl;    -   R¹⁶ is —C(═O)NR¹R², —C(═N—CN)NR¹R², —P(═O)R¹R², or —C(═O)R¹¹;    -   R¹ and R² are independently hydrogen, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,        C₁-C₆aminoalkyl, C₂-C₆alkenyl, or C₂-C₆alkynyl;    -   R³ is hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl, or        C₁-C₆deuteroalkyl;    -   R⁴ is hydrogen, deuterium, halogen, —CN, —OR^(b), —SR^(b),        —S(═O)R^(a), —S(═O)₂R^(a), —NO₂, —NR^(c)R^(d), —NHS(═O)₂R^(a),        —S(═O)₂NR^(c)R^(d), —C(═O)R^(a), —OC(═O)R^(a), —C(═O)OR^(b),        —OC(═O)OR^(b), —C(═O)NR^(c)R^(d), —OC(═O)NR^(c)R^(d),        —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a), —NR^(b)C(═O)OR^(b),        C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl,        C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₂-C₆alkenyl, or        C₂-C₆alkynyl;    -   or R³ and R⁴ are taken together to form an optionally        substituted ring;    -   each X is independently —CR^(x)— or —N—;    -   each R^(x) is independently hydrogen, deuterium, halogen, —CN,        —OR^(b), —SR^(b), —S(═O)R^(a), —S(═O)₂R^(a), —NO₂, —NR^(c)R^(d),        —NHS(═O)₂R^(a), —S(═O)₂NR^(c)R^(d), —C(═O)R^(a), —OC(═O)R^(a),        —C(═O)OR^(b), —OC(═O)OR^(b), —C(═O)NR^(c)R^(d),        —OC(═O)NR^(c)R^(d), —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a),        —NR^(b)C(═O)OR^(b), C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,        C₂-C₆alkenyl, or C₂-C₆alkynyl;    -   R⁵ is halogen, —CN, —OR⁸, —SR⁸, —S(═O)R⁷, —S(═O)₂R⁷, —NO₂,        —NR⁹R¹⁰, —NR⁸S(═O)R⁷, —NR⁸S(═O)₂R⁷, —S(═O)₂NR⁹R¹⁰, —C(═N—CN)R⁷,        —C(═O)R⁷, 13 OC(═N—CN)R⁷, —OC(—O)R⁷, —C(═N—CN)OR⁸, —C(═O)OR⁸,        —OC(═N—CN)OR⁸, —OC(═O)OR⁸, —C(═N—CN)NR⁹R¹⁰, —C(═O)NR⁹R¹⁰,        —OC(═N—CN)NR⁹R¹⁰, —OC(═O)NR⁹R¹⁰, —NR⁸C(═N—CN)NR⁹R¹⁰,        —NR⁸C(═O)NR⁹R¹⁰, —NR⁸C(═N—CN)R⁷, —NR⁸C(═N—OH)R⁷,        —NR⁸C(═N—CN)OR⁸, —NR⁸C(═O)OR⁸, —NR⁸S(═O)(═NR⁸)R⁷, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,        C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl,        alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one or        more oxo, deuterium, halogen, —CN, —OR^(b), —NR^(c)R^(d),        —C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,        C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,        cycloalkyl, heterocycloalkyl, aryl, heteroaryl,        C₁-C₆alkyl(cycloalkyl), C₁-C₆alkyl(heterocycloalkyl),        C₁-C₆alkyl(aryl), or C₁-C₆alkyl(heteroaryl); wherein each alkyl,        alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one or        more oxo, deuterium, halogen, —CN, —OR^(b), —NR^(c)R^(d),        —C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆alkyl, or        C₁-C₆haloalkyl;    -   or R^(x) and R⁵ are taken together to form ring D optionally        substituted with one or more R^(D);    -   Ring D is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;    -   each R^(D) is independently hydrogen, deuterium, halogen, —CN,        —OR^(b), —SR^(b), —S(═O)R^(a), —S(═O)₂R^(a), —NO₂, —NR^(c)R^(d),        —NHS(═O)₂R^(a), —S(═O)₂NR^(c)R^(d), —C(═O)R^(a), —OC(═O)R^(a),        —C(═O)OR^(b), —OC(═O)OR^(b), —C(═O)NR^(c)R^(d),        —OC(═O)NR^(c)R^(d), —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a),        —NR^(b)C(═O)OR^(b), C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,        C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl,        or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl is independently        optionally substituted with one or more oxo, deuterium, halogen,        —CN, —OR^(b), —NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b),        —C(═O)NR^(c)R^(d), C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   or two R^(D) on the same carbon are taken together to form an        oxo;    -   R⁷ is C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl,        C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,        cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each        alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one or        more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH₂, —C(═O)Me,        —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   each R⁸ is independently hydrogen, CN, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,        C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl,        alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one or        more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH₂, —C(═O)Me,        —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   R⁹ and R¹⁰ are independently hydrogen, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,        C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl,        alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one or        more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH₂, —C(═O)Me,        —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, C₁-C₆deuteroalkyl,        C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆hydroxydeuteroalkyl,        cycloalkyl, or heterocycloalkyl;    -   or R⁹ and R¹⁰ are taken together with the nitrogen atom to which        they are attached to form a heterocycloalkyl optionally        substituted with one or more oxo, deuterium, halogen, —CN, —OH,        —OMe, —NH₂, —C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or        C₁-C₆haloalkyl;    -   or R⁸ and R⁹ are taken together with the atoms to which they are        attached to form a heterocycloalkyl optionally substituted with        one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH₂,        —C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   R¹¹ is C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl,        C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,        cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each        alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one or        more R^(11a);    -   each R^(11a) is independently deuterium, halogen, —CN, —OR^(b),        —SR^(b), —S(═O)R^(a), —S(═O)₂R^(a), —NO₂, —NR^(c)R^(d),        —NHS(═O)₂R^(a), —S(═O)₂NR^(c)R^(d), —C(═O)R^(a), —OC(═O)R^(a),        —C(═O)OR^(b), —OC(═O)OR^(b), —C(═O)NR^(c)R^(d),        —OC(═O)NR^(c)R^(d), —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a),        —NR^(b)C(═O)OR^(b), C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,        C₂-C₆alkenyl, or C₂-C₆alkenyl;    -   each R^(a) is independently C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,        C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl,        or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl is independently        optionally substituted with one or more oxo, deuterium, halogen,        —CN, —OH, —OMe, —NH₂, —C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl,        or C₁-C₆haloalkyl;    -   each R^(b) is independently hydrogen, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,        C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl,        alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one or        more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH₂, —C(═O)Me,        —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   each R^(c) and R^(d) is independently hydrogen, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,        C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl,        alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one or        more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH₂, —C(═O)Me,        —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   or R^(c) and R^(d) are taken together with the nitrogen atom to        which they are attached to form a heterocycloalkyl optionally        substituted with one or more oxo, deuterium, halogen, —CN, —OH,        —OMe, —NH₂, —C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or        C₁-C₆haloalkyl.

In some embodiments of a compound of Formula (XII), Ring B is aryl orheteroaryl. In some embodiments of a compound of Formula (XII), Ring Bis aryl. In some embodiments of a compound of Formula (XII), Ring B isphenyl. In some embodiments of a compound of Formula (XII), Ring B isheteroaryl. In some embodiments of a compound of Formula (XII), Ring Bis 5- or 6-membered heteroaryl. In some embodiments of a compound ofFormula (XII), Ring B is 6-membered heteroaryl. In some embodiments of acompound of Formula (XII), Ring B is pyridyl.

Also disclosed herein is a compound of Formula (XII′), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof:

wherein:

-   -   R¹⁶ is —C(═O)NR¹R², —C(═N—CN)NR¹R², —P(═O)R¹R², or —C(═O)R¹¹;    -   R¹ and R² are independently hydrogen, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,        C₁-C₆aminoalkyl, C₂-C₆alkenyl, or C₂-C₆alkynyl;    -   R³ is hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl, or        C₁-C₆deuteroalkyl;    -   R⁴ is hydrogen, deuterium, halogen, —CN, —OR^(b), —SR^(b),        —S(═O)R^(a), —S(═O)₂R^(a), —NO₂, —NR^(c)R^(d), —NHS(═O)₂R^(a),        —S(═O)₂NR^(c)R^(d), —C(═O)R^(a), —OC(═O)R^(a), —C(═O)OR^(b),        —OC(═O)OR^(b), —C(═O)NR^(c)R^(d), —OC(═O)NR^(c)R^(d),        —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a), —NR^(b)C(═O)OR^(b),        C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl,        C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₂-C₆alkenyl, or        C₂-C₆alkynyl;    -   or R³ and R⁴ are taken together to form an optionally        substituted ring;    -   L is a bond or —C(═O)—;    -   Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;        each optionally substituted with one or more R^(A);    -   each R^(A) is independently deuterium, halogen, —CN, —OR^(b),        —SR^(b), —S(═O)R^(a), —S(═O)₂R^(a), —NO₂, —NR^(c)R^(d),        —NHS(═O)₂R^(a), —S(═O)₂NR^(c)R^(d), —C(═O)R^(a), —OC(═O)R^(a),        —C(═O)OR^(b), —OC(═O)OR^(b), —C(═O)NR^(c)R^(d),        —OC(═O)NR^(c)R^(d), —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a),        —NR^(b)C(═O)OR^(b), C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,        C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl,        or heteroaryl; wherein each alkyl, alkenyl, alkenyl, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl is independently        optionally substituted with one or more oxo, deuterium, halogen,        —CN, —OR^(b), —NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b),        —C(═O)NR^(c)R^(d), C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   or two R^(A) on the same carbon are taken together to form an        oxo;    -   each X is independently —CR^(x)— or —N—;    -   each R^(x) is independently hydrogen, deuterium, halogen, —CN,        —OR^(b), —SR^(b), —S(═O)R^(a), —S(═O)₂R^(a), —NO₂, —NR^(c)R^(d),        —NHS(═O)₂R^(a), —S(═O)₂NR^(c)R^(d), —C(═O)R^(a), —OC(═O)R^(a),        —C(═O)OR^(b), —OC(═O)OR^(b), —C(═O)NR^(c)R^(d),        —OC(═O)NR^(c)R^(d), —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a),        —NR^(b)C(═O)OR^(b), C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,        C₂-C₆alkenyl, or C₂-C₆alkynyl;    -   R⁵ is halogen, —CN, —OR⁸, —SR⁸, —S(═O)R⁷, —S(═O)₂R⁷, —NO₂,        —NR⁹R¹⁰, —NR⁸S(═O)R⁷, —NR⁸S(═O)₂R⁷, —S(═O)₂NR⁹R¹⁰, —C(═N—CN)R⁷,        —C(═O)R⁷, 13 OC(═N—CN)R⁷, —OC(—O)R⁷, —C(═N—CN)OR⁸, —C(═O)OR⁸,        —OC(═N—CN)OR⁸, —OC(═O)OR⁸, —C(═N—CN)NR⁹R¹⁰, —C(═O)NR⁹R¹⁰,        —OC(═N—CN)NR⁹R¹⁰, —OC(═O)NR⁹R¹⁰, —NR⁸C(═N—CN)NR⁹R¹⁰,        —NR⁸C(═O)NR⁹R¹⁰, —NR⁸C(═N—CN)R⁷, —NR⁸C(═N—OH)R⁷,        —NR⁸C(═N—CN)OR⁸, —NR⁸C(═O)OR⁸, —NR⁸S(═O)(═NR⁸)R⁷, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,        C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl,        alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one or        more oxo, deuterium, halogen, —CN, —OR^(b), —NR^(c)R^(d),        —C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,        C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,        cycloalkyl, heterocycloalkyl, aryl, heteroaryl,        C₁-C₆alkyl(cycloalkyl), C₁-C₆alkyl(heterocycloalkyl),        C₁-C₆alkyl(aryl), or C₁-C₆alkyl(heteroaryl); wherein each alkyl,        alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one or        more oxo, deuterium, halogen, —CN, —OR^(b), —NR^(c)R^(d),        —C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆alkyl, or        C₁-C₆haloalkyl;    -   or R^(x) and R⁵ are taken together to form ring D optionally        substituted with one or more R^(D);    -   Ring D is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;    -   each R^(D) is independently hydrogen, deuterium, halogen, —CN,        —OR^(b), —SR^(b), —S(═O)R^(a), —S(═O)₂R^(a), —NO₂, —NR^(c)R^(d),        —NHS(═O)₂R^(a), —S(═O)₂NR^(c)R^(d), —C(═O)R^(a), —OC(═O)R^(a),        —C(═O)OR^(b), —OC(═O)OR^(b), —C(═O)NR^(c)R^(d),        —OC(═O)NR^(c)R^(d), —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a),        —NR^(b)C(═O)OR^(b), C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,        C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl,        or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl is independently        optionally substituted with one or more oxo, deuterium, halogen,        —CN, —OR^(b), —NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b),        —C(═O)NR^(c)R^(d), C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   or two R^(D) on the same carbon are taken together to form an        oxo;    -   R⁷ is C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl,        C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,        cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each        alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one or        more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH₂, —C(═O)Me,        —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   each R⁸ is independently hydrogen, CN, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,        C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl,        alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one or        more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH₂, —C(═O)Me,        —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   R⁹ and R¹⁰ are independently hydrogen, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,        C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl,        alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one or        more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH₂, —C(═O)Me,        —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, C₁-C₆deuteroalkyl,        C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆hydroxydeuteroalkyl,        cycloalkyl, or heterocycloalkyl;    -   or R⁹ and R¹⁰ are taken together with the nitrogen atom to which        they are attached to form a heterocycloalkyl optionally        substituted with one or more oxo, deuterium, halogen, —CN, —OH,        —OMe, —NH₂, —C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or        C₁-C₆haloalkyl;    -   or R⁸ and R⁹ are taken together with the atoms to which they are        attached to form a heterocycloalkyl optionally substituted with        one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH₂,        —C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   R¹¹ is C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl,        C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,        cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each        alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one or        more R^(11a);    -   each R^(11a) is independently deuterium, halogen, —CN, —OR^(b),        —SR^(b), —S(═O)R^(a), —S(═O)₂R^(a), —NO₂, —NR^(c)R^(d),        —NHS(═O)₂R^(a), —S(═O)₂NR^(c)R^(d), —C(═O)R^(a), —OC(═O)R^(a),        —C(═O)OR^(b), —OC(═O)OR^(b), —C(═O)NR^(c)R^(d),        —OC(═O)NR^(c)R^(d), —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a),        —NR^(b)C(═O)OR^(b), C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,        C₂-C₆alkenyl, or C₂-C₆alkenyl;    -   each R^(a) is independently C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,        C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl,        or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl is independently        optionally substituted with one or more oxo, deuterium, halogen,        —CN, —OH, —OMe, —NH₂, —C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl,        or C₁-C₆haloalkyl;    -   each R^(b) is independently hydrogen, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,        C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl,        alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one or        more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH₂, —C(═O)Me,        —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   each R^(c) and R^(d) is independently hydrogen, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,        C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl,        alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one or        more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH₂, —C(═O)Me,        —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   or R^(c) and R^(d) are taken together with the nitrogen atom to        which they are attached to form a heterocycloalkyl optionally        substituted with one or more oxo, deuterium, halogen, —CN, —OH,        —OMe, —NH₂, —C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or        C₁-C₆haloalkyl.

In some embodiments of a compound of Formula (XII) or (XII′), L is abond. In some embodiments of a compound of Formula (XII) or (XII′), L is—C(═O)—.

In some embodiments of a compound of Formula (XII) or (XII′), -L-Ring Ais absent.

In some embodiments of a compound of Formula (XII) or (XII′), Ring A isheterocycloalkyl or heteroaryl; each optionally substituted with one ormore ^(A). In some embodiments of a compound of Formula (XII) or (XII′),Ring A is a 5-membered heterocycloalkyl or a 5-membered heteroaryl; eachoptionally substituted with one or more R^(A). In some embodiments of acompound of Formula (XII) or (XII′), Ring A is heteroaryl optionallysubstituted with one or more R^(A).

In some embodiments of a compound of Formula (XII) or (XII′), each R^(A)is independently deuterium, halogen, —CN, —OR^(b), —NR^(c)R^(d),—C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d), —OC(═O)NR^(c)R^(d),C₁-C₆alkyl, C₁-C₆haloalkyl, or C₁-C₆deuteroalkyl. In some embodiments ofa compound of Formula (XII) or (XII′), each R^(A) is independentlydeuterium, halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, or C₁-C₆deuteroalkyl. Insome embodiments of a compound of Formula (XII) or (XII′), each R^(A) isindependently halogen or C₁-C₆alkyl. In some embodiments of a compoundof Formula (XII) or (XII′), each R^(A) is independently C₁-C₆alkyl.

In some embodiments of a compound of Formula (XII), the compound is ofFormula (XIIa):

In some embodiments of a compound of Formula (XII), the compound is ofFormula (XIIb):

In some embodiments of a compound of Formula (XII), (XII′), (XIIa),(XIIb), or (XIIc), R⁴ is hydrogen, deuterium, halogen, —CN, —OR^(b),—NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d),—OC(═O)NR^(c)R^(d), C₁-C₆alkyl, C₁-C₆haloalkyl, or C₁-C₆deuteroalkyl. Insome embodiments of a compound of Formula (XII), (XII′), (XIIa), (XIIb),or (XIIc), R⁴ is hydrogen or —OR^(b). In some embodiments of a compoundof Formula (XII), (XII′), (XIIa), (XIIb), or (XIIc), R⁴ is —OR^(b). Insome embodiments of a compound of Formula (XII), (XII′), (XIIa), (XIIb),or (XIIc), R⁴ is hydrogen. In some embodiments of a compound of Formula(XII), R⁴ is —P(═O)R^(b)R^(b). In some embodiments of a compound ofFormula (XII), (XII′), (XIIa), (XIIb), or (XIIc), R⁴ is —S(═O)₂R^(a).

In some embodiments of a compound of Formula (XII), (XII′), (XIIa),(XIIb), or (XIIc), each X is —N—. In some embodiments of a compound ofFormula (XII), (XII′), (XIIa), (XIIb), or (XIIc) each X is —CR^(X). Insome embodiments of a compound of Formula (XII), (XII′), (XIIa), (XIIb),or (XIIc), two X are —N— and the other is —CR^(X)—. In some embodimentsof a compound of Formula (XII), (XII′), (XIIa), (XIIb), or (XIIc), one Xis —N— and the others are —CR^(X)—. In some embodiments of a compound ofFormula (XII), (XIV), (XIIa), (XIIb), or (XIIc), each X is —CH—. In someembodiments of a compound of Formula (XII), (XII′), (XIIa), (XIIb), or(XIIc), two X are —N— and the other is —CH—. In some embodiments of acompound of Formula (XII), (XII′), (XIIa), (XIIb), or (XIIc), one X is—N— and the others are —CH—. In some embodiments of a compound ofFormula (XII), (XII′), (XIIa), (XIIb), or (XIIc),

is

In some embodiments of a compound of Formula (XII), (XII′), (XIIa),(XIIb), or (XIIc),

is

In some embodiments of a compound of Formula (XII), (XII′), (XIIa),(XIIb), or (XIIc),

In some embodiments of a compound of Formula (XII), (XII′), (XIIa),(XIIb), or (XIIc), each R^(X) is independently hydrogen, deuterium,halogen, —CN, —OR^(b), —NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b),C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, orC₁-C₆aminoalkyl. In some embodiments of a compound of Formula (XII),(XII′), (XIIa), (XIIb), or (XIIc), each R^(X) is independently hydrogen,deuterium, halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, or C₁-C₆deuteroalkyl. Insome embodiments of a compound of Formula (XII), (XII′), (XIIa), (XIIb),or (XIIc), each R^(X) is independently hydrogen, deuterium, or halogen.

In some embodiments of a compound of Formula (XII), (XII′), (XIIa),(XIIb), or (XIIc),

is

In some embodiments of a compound of Formula (XII), (XII′), (XIIa),(XIIb), or (XIIc),

is

In some embodiments of a compound of Formula (XII), (XII′), (XIIa),(XIIb), or (XIIc),

is

In some embodiments of a. compound of Formula (XII), (XII′), (XIIa),(XIIb), or (XIIc), R³ is hydrogen or C₁-C₆alkyl. In some embodiments ofa compound of Formula (XII), (XII′), (XIIa), (XIIb), or (XIIc), R³ ishydrogen.

In some embodiments of a compound of Formula (XII), (XII′), (IIa),(IIb), or (XIIc), R¹⁶ is —C(═O)NR¹R² or —C(═O)R¹¹. In some embodimentsof a compound of Formula (XII), (XII′), (XIIa), (XIIb), or (XIIc), R¹⁶is —C(═O)NR¹R². In some embodiments of a compound of Formula (XII),(XII′), (XIIa), (XIIb), or (XIIc), R¹⁶ is —C(═N—CN)NR¹R². In someembodiments of a compound of Formula (XII), (XII′), (XIIa), (XIIb), or(XIIc), R¹⁶ is —P(═O)R¹R². In some embodiments of a compound of Formula(XII), (XII′), (XIIa), (XIIb), or (XIIc), R¹⁶ is —C(═O)R¹¹.

In some embodiments of a compound of Formula (XII), (XII′), (XIIa),(XIIb), or (XIIc), R¹ and R² are independently hydrogen, C₁-C₆alkyl,C₁-C₆haloalkyl, or C₁-C₆deuteroalkyl. In some embodiments of a compoundof Formula (XII), (XII′), (XIIa), (XIIb), or (XIIc), R¹ and R² areindependently hydrogen or C₁-C₆deuteroalkyl. In some embodiments of acompound of Formula (XII), (XII′), (XIIa), (XIIb), or (XIIc), R¹ and R²are independently C₁-C₆alkyl. In some embodiments of a compound ofFormula (XII), (XII′), (XIIa), (XIIb), or (XIIc), R¹ is hydrogen. Insome embodiments of a compound of Formula (XII), (XII′), (XIIa), (XIIb),or (XIIc), R² is C₁-C₆alkyl or C₁-C₆deuteroalkyl. In some embodiments ofa compound of Formula (XII), (XII′), (XIIa), (XIIb), or (XIIc), R² isC₁-C₆deuteroalkyl. In some embodiments of a compound of Formula (XII),(XII′), (XIIa), (XIIb), or (XIIc), R² is C₁-C₆alkyl.

In some embodiments of a compound of Formula (XII), (XII′), (XIIa),(XIIb), or (XIIc), R¹¹ is C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl,C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, cycloalkyl, heterocycloalkyl, aryl,or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl,and heteroaryl is independently optionally substituted with one or moreR^(11a). In some embodiments of a compound of Formula (XII), (XII′),(XIIa), (XIIb), or (XIIc), R¹¹ is C₁-C₆alkyl, C₁-C₆haloalkyl,C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, cycloalkyl, orheterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkylis independently optionally substituted with one or more R^(11a). Insome embodiments of a compound of Formula (XII), (XII′), (XIIa), (XIIb),or (XIIc), R¹¹ is C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl,cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, andheterocycloalkyl is independently optionally substituted with one ormore R^(11a). In some embodiments of a compound of Formula (XII),(XII′), (XIIa), (XIIb), or (XIIc), R¹¹ is C₁-C₆alkyl, C₁-C₆haloalkyl, orcycloalkyl; wherein each alkyl and cycloalkyl is independentlyoptionally substituted with one or more R^(11a). In some embodiments ofa compound of Formula (XII), (XII′), (XIIa), (XIIb), or (XIIc), R¹¹ isC₁-C₆alkyl or cycloalkyl; wherein each alkyl and cycloalkyl isindependently optionally substituted with one or more R^(11a). In someembodiments of a compound of Formula (XII), (XII′), (XIIa), (XIIb), or(XIIc), R¹¹ is C₁-C₆alkyl, C₁-C₆deuteroalkyl, C₁-C₆haloalkyl, orcycloalkyl. In some embodiments of a compound of Formula (XII), (XII′),(XIIa), (XIIb), or (XIIc), is C₁-C₆alkyl, C₁-C₆haloalkyl, or cycloalkyl.In some embodiments of a compound of Formula (XII), (XII′), (XIIa),(XIIb), or (XIIc), R¹¹ is C₁-C₆deuteroalkyl. In some embodiments of acompound of Formula (XII), (XII′), (XIIa), (XIIb), or (XIIc), R¹¹ isC₁-C₆alkyl, In some embodiments of a compound of Formula (XII), (XII′),(XIIa), (XIIb), or (XIIc), R¹¹ is cycloalkyl. In some embodiments of acompound of Formula (XII), (XII′), (XIIa), (XIIb), or (XIIc), R¹¹ isC₁-C₆alkyl, C₁-C₆deuteroalkyl, or cycloalkyl.

In some embodiments of a compound of Formula (XII), (XII′), (XIIa),(XIIb), or (XIIc), each R^(11a) is independently deuterium, halogen,—CN, —OR^(b), NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d),C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, orC₁-C₆aminoalkyl. In some embodiments of a compound of Formula (XII),(XII′), (XIIa), (XIIb), or (XIIc), each R^(11a) is independentlydeuterium, halogen, —CN, —OR^(b), NR^(c)R^(d), C₁-C₆alkyl,C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, orC₁-C₆aminoalkyl. In some embodiments of a compound of Formula (XII),(XII′), (XIIa), (XIIb), or (XIIc), each R^(11a) is independentlydeuterium, halogen, —CN, —OR^(b), NR^(c)R^(d), C₁-C₆alkyl,C₁-C₆haloalkyl, or C₁-C₆deuteroalkyl. In some embodiments of a compoundof Formula (XII), (XII′), (XIIa), (XIIb), or (XIIc), each R^(11a) isindependently deuterium, halogen, —CN, —OR^(b), NR^(c)R^(d), orC₁-C₆alkyl. In some embodiments of a compound of Formula (XII), (XII′),(XIIa), (XIIb), or (XIIc), each R^(11a) is independently deuterium,halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, or C₁-C₆deuteroalkyl. In someembodiments of a compound of Formula (XII), (XII′), (XIIa), (XIIb), or(XIIc), each R^(11a) is independently deuterium, halogen, or C₁-C₆alkyl.

In some embodiments of a compound of Formula (XII), (XII′), (XIIa), or(XIIb), R⁵ is halogen, —CN, —OR^(b), —S(═OR)⁷, —S(═O)₂R⁷, —NO₂, —NR⁹R¹⁰,—NHS(═O)₂R⁷, —S(═O)₂NR⁹R¹⁰, —C(═N—CN)R⁷, —C(═O)R⁷, —OC(═N—CN)R⁷,—OC(═O)R⁷, —C(═N—CN)OR⁸, —C(═O)OR⁸, —OC(═N—CN)OR⁸, —OC(═O)OR⁸,—C(═N—CN)NR⁹R¹⁰, —C(═O)NR⁹R¹⁰, —OC(═N—CN)NR⁹R¹⁰, —OC(═O)NR⁹R¹⁰,—NR⁸C(═N—CN)NR⁹R¹⁰, —NR⁸C(═O)NR⁹R¹⁰, —NR⁸C(═N—CN)R⁷, —NR⁸C(═N—OH)R⁷,—NR⁸C(═N—CN)OR⁸, —NR⁸C(═O)OR⁸, —NR⁸S(═O)(=NR⁸)R⁷, C₁-C₆alkyl,C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl, orheteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is independently optionallysubstituted with one or more oxo, deuterium, halogen, —CN, —OR^(b),—NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆alkyl,C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,C₁-C₆heteroalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl,heterocycloalkyl, aryl, heteroaryl, C₁-C₆alkyl(cycloalkyl),C₁-C₆alkyl(heterocycloalkyl), C₁-C₆alkyl(aryl), orC₁-C₆alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is independently optionallysubstituted with one or more oxo, deuterium, halogen, —CN, —OR^(b),NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆alkyl,or C₁-C₆haloalkyl.

In some embodiments of a compound of Formula (XII), (XII′), (XIIa), or(XIIb), R⁵ is halogen, —CN, —OR^(b), NR⁹R¹⁰, —C(═O)R⁷, —C(═O)OR⁸,—C(═O)NR⁹R¹⁰, —NR⁸C(═O)NR⁹R¹⁰, —NR⁸C(═N—CN)R⁷, —NR⁸C(═O)R⁷,—NR⁸C(═O)OR⁸, —NR⁸S(═O)(═NR⁸)R⁷, C₁-C₆alkyl, C₁-C₆haloalkyl,C₁-C₆deuteroalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl,heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is independently optionallysubstituted with one or more oxo, deuterium, halogen, —CN, —OR^(b),—NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆alkyl,or C₁-C₆haloalkyl.

In some embodiments of a compound of Formula (XII), (XII′), (VIIa), or(XIIb), R⁵ is halogen, —CN, —OR^(b), NR⁹R¹⁰, —C(═O)R⁷, —C(═O)OR⁸,—C(═O)NR⁹R¹⁰, —NR⁸C(═O)NR⁹R¹⁰, —NR⁸C(═N—CN)R⁷, —NR⁸C(═O)R⁸,—NR⁸S(═O)(═NR⁸)R⁷, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl,C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl, orheteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, andheteroaryl is independently optionally substituted with one or more oxo,deuterium, halogen, —CN, —OR^(b), —NR^(c)R^(d), —C(═O)R^(a),—C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆alkyl, or C₁-C₆haloalkyl.

In some embodiments of a compound of Formula (XII), (XII′), (XIIa), or(XIIb), R⁵ is halogen, —CN, —OR^(b), NR⁹R¹⁰, —C(═O)R⁷, —C(═O)OR⁸,—C(═O)NR⁹R¹⁰, —NR⁸C(═O)NR⁹R¹⁰, —NR⁸C(═N—CN)R⁷, —NR⁸C(═O)OR⁸,—NR⁸S(═O)(═NR⁸)R⁷, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl,C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl, orheteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, andheteroaryl is independently optionally substituted with one or more oxo,deuterium, halogen, —CN, —OR^(b), —NR^(c)R^(d), —C(═O)R^(a),—C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆alkyl, or C₁-C₆haloalkyl.

In some embodiments of a compound of Formula (XII), (XII′), (XIIa), or(XIIb), R⁵ is —OR⁸, —NR⁹R¹⁰, —C(═O)R⁷, —C(═O)OR⁸, —C(═O)NR⁹R¹⁰,—NR⁸C(═O)NR⁹, R¹⁰, —NR⁸C(═N—CN)R⁷, —NR⁸C(═O)R⁷, —NR⁸C(═O)OR⁸,—NR⁸S(═O)(═NR⁸)R⁷, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl isindependently optionally substituted with one or more oxo, deuterium,halogen, —CN, —OR^(b), —NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b),—C(═O)NR^(c)R^(d), C₁-C₆alkyl, or C₁-C₆haloalkyl.

In some embodiments of a compound of Formula (XII), (XII′), (XIIa), or(XIIb), R⁵ is —OR⁸, —NR⁹R¹⁰, —C(═O)R⁷, —C(═O)OR⁸, —C(═O)NR⁹R¹⁰,—NR⁸C(═O)NR⁹, R¹⁰, —NR⁸C(═N—CN)R⁷, —NR⁸C(═O)R⁷, —NR⁸S(═O)(═NR⁸)R⁷,cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein eachcycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independentlyoptionally substituted with one or more oxo, deuterium, halogen, —CN,—OR^(b), —NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d),C₁-C₆alkyl, or C₁-C₆haloalkyl. In some embodiments of a compound ofFormula (XII), (XII′), (XIIa), or (XIIb), R⁵ is —OR⁸, —NR⁹R¹⁰,—NR⁸C(═O)R⁷, —NR⁸C(═N—CN)R⁷, —NR⁸S(═O)(═NR⁸)R⁷, or aryl optionallysubstituted with one or more deuterium, halogen, —CN, —OR^(b),—NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆alkyl,or C₁-C₆haloalkyl.

In some embodiments of a compound of Formula (XII), (XII′), (XIIa), or(XIIb), R⁵ is —OR⁸, —NR⁹R¹⁰, —NR⁸C(═N—CN)R⁷, —NR⁸S(═O)(═NR⁸)R⁷I, or aryloptionally substituted with one or more deuterium, halogen, —CN,—OR^(b), —NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d),C₁-C₆alkyl, or C₁-C₆haloalkyl.

In some embodiments of a compound of Formula (XII), (XII′), (XIIa), or(XIIb), R⁵ is —OR⁸, —NR⁹R¹⁰, —NR⁸C(═O)R⁷, cycloalkyl heterocycloalkyl,aryl, or heteroaryl; wherein each cycloalkyl, heterocycloalkyl, aryl,and heteroaryl is independently optionally substituted with one or moreoxo, deuterium, halogen, —CN, —OR^(b), —NR^(c)R^(d), —C(═O)R^(a),—C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆alkyl, or C₁-C₆haloalkyl. In someembodiments of a compound of Formula (XII), (XII′), (XIIa), or (XIIb),R⁵ is aryl optionally substituted with one or more oxo, deuterium,halogen, —CN, —OR^(b), —NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b),—C(═O)NR^(c)R^(d), C₁-C₆alkyl, or C₁-C₆haloalkyl.

In some embodiments of a compound of Formula (XII), (XII′), (XIIa), or(XIIb), R⁵ is —NR⁹R¹⁰, —NR⁸C(═O)NR⁹R¹⁰, or —NR⁸C(═N—CN)R⁷.

In some embodiments of a compound of Formula (XII), (XII′), (XIIa), or(XIIb), R⁵ is —NR⁹R¹⁰,

In some embodiments of a compound of Formula (XII), (XII′), (XIIa), or(XIIb), R⁵ is —NR⁹R¹⁰ or —NR⁸C(═O)NR⁹R¹⁰.

In some embodiments of a compound of Formula (XII), (XII′), (XIIa), or(XIIb), R⁵ is —NR⁸C(═N—CN)R⁷.

In some embodiments of a compound of Formula (XII), (XII′), (XIIa), or(XIIb), R⁵ is —NR⁸S(═O)(═NR⁸)R⁷.

In some embodiments of a compound of Formula (XII), (XII′), (XIIa), or(XIIb), R⁵ is —NR⁸C(═O)NR⁹R¹⁰ or —NR⁸C(═O)R⁷.

In some embodiments of a compound of Formula (XII), (XII′), (XIIa), or(XIIb), R⁵ is —NR⁸C(═O)NR⁹R¹⁰.

In some embodiments of a compound of Formula (XII), (XII′), (XIIa), or(XIIb), R⁵ is —NR⁸C(═O)R⁷.

In some embodiments of a compound of Formula (XII), (XII′), (XIIa), or(XIIb), R⁵ is not —NR⁸C(═O)R⁷.

In some embodiments of a compound of Formula (XII), (XII′), (XIIa), or(XIIb), R⁵ is —NR⁸C(═O)NR⁹R¹⁰ or heterocycloalkyl optionally substitutedwith one or more oxo, deuterium, halogen, —CN, —OR^(b), —NR^(c)R^(d),—C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆alkyl,C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,C₁-C₆heteroalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl,heterocycloalkyl, aryl, heteroaryl, C₁-C₆alkyl(cycloalkyl),C₁-C₆alkyl(heterocycloalkyl), C₁-C₆alkyl(aryl), orC₁-C₆alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl,cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independentlyoptionally substituted with one or more oxo, deuterium, halogen, —CN,—OR^(b), —NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d),C₁-C₆alkyl, or C₁-C₆haloalkyl.

In some embodiments of a compound of Formula (XII), (XII′), (XIIa), or(XIIb), R⁵ is heterocycloalkyl optionally substituted with one or moreoxo, deuterium, halogen, —CN, —OR^(b), NR^(c)R^(d), —C(═O)R^(a),—C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆alkyl, C₁-C₆haloalkyl,C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₁-C₆heteroalkyl,C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl,heteroaryl, C₁-C₆alkyl(cycloalkyl), C₁-C₆alkyl(heterocycloalkyl),C₁-C₆alkyl(aryl), C₁-C₆alkyl(heteroaryl); wherein each alkyl, alkenyl,alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl isindependently optionally substituted with one or more oxo, deuterium,halogen, —CN, —OR^(b), —NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b),—C(═O)NR^(c)R^(d), C₁-C₆alkyl, C₁-C₆haloalkyl.

In some embodiments of a compound of Formula (XII), (XII′), (XIIa), or(XIIb), R⁵ is heterocycloalkyl optionally substituted with one or moreoxo, deuterium, halogen, —CN, —OR^(b), —NR^(c)R^(d), C₁-C₆alkyl,C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,C₁-C₆heteroalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl,heterocycloalkyl, aryl, heteroaryl, C₁-C₆alkyl(cycloalkyl), orC₁-C₆alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl,cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independentlyoptionally substituted with one or more oxo, deuterium, halogen, —CN,—OR^(b), —NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d),C₁-C₆alkyl, or C₁-C₆haloalkyl.

In some embodiments of a compound of Formula (XII), (XII′), (XIIa), or(XIIb), R⁵ is heterocycloalkyl optionally substituted with one or moreoxo, halogen, —OR^(b), C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl,C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, C₂-C₆alkynyl,cycloalkyl, heterocycloalkyl, aryl, C₁-C₆alkyl(cycloalkyl), orC₁-C₆alkyl(heterocycloalkyl); wherein each alkyl, alkynyl, cycloalkyl,heterocycloalkyl, and aryl is independently optionally substituted withone or more oxo, deuterium, halogen, —CN, —OR^(b), —NR^(c)R^(d),—C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆alkyl, orC₁-C₆haloalkyl.

In some embodiments of a compound of Formula (XII), (XII′), (XIIa), or(XIIb), the heterocycloalkyl of R⁵ is

In some embodiments of a compound of Formula (XII), (XII′), (XIIa), or(XIIb), the heterocycloalkyl of R⁵ is

In some embodiments of a. compound of Formula (XII), (XII′), (XIIa), or(XIIb), R⁷ is C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, cycloalkyl,heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is independently optionallysubstituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe,—NH₂, —C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl. Insome embodiments of a compound of Formula (XII), (XII′), (XIIa), or(XIIb), R⁷ is C₁-C₆alkyl, cycloalkyl, or heterocycloalkyl; wherein eachalkyl, cycloalkyl, or heterocycloalkyl is independently optionallysubstituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe,—NH₂, —C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl. Insome embodiments of a compound of Formula (XII), (XII′), (XIIa), or(XIIb), R⁷ is C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, orcycloalkyl; wherein each alkyl and cycloalkyl is independentlyoptionally substituted with one or more oxo, deuterium, halogen, —CN,—OH, —OMe, —NH₂, —C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, orC₁-C₆haloalkyl. In some embodiments of a compound of Formula (XII),(XII′), (XIIa), or (XIIb), R⁷ is C₁-C₆alkyl or cycloalkyl; wherein eachalkyl and cycloalkyl is independently optionally substituted with one ormore oxo, deuterium, halogen, —CN, —OH, —OMe, —NH₂, —C(═O)Me, —C(═O)OH,—C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl. In some embodiments of acompound of Formula (XII), (XII′), (XIIa), or (XIIb), R⁷ is cycloalkyloptionally substituted with one or more oxo, deuterium, halogen, —CN,—OH, —OMe, —NH₂, —C(═O)OMe, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, orC₁-C₆haloalkyl. In some embodiments of a compound of Formula (XII),(XII′), (XIIa), or (XIIb), R⁷ is unsubstituted cycloalkyl. In someembodiments of a compound of Formula (XII), (XII′), (XIIa), or (XIIb),R⁷ is heterocycloalkyl optionally substituted with one or more oxo,deuterium, halogen, —CN, —OH, —OMe, —NH₂, —C(═O)Me, —C(═O)OH, —C(═O)OMe,C₁-C₆alkyl, or C₁-C₆haloalkyl. In some embodiments of a compound ofFormula (XII), (XII′), (XIIa), or (XIIb), R⁷ is unsubstitutedheterocycloalkyl.

In some embodiments of a compound of Formula (XII), (XII′), (XIIa), or(XIIb), R⁸ is hydrogen, CN, C₁-C₆alkyl, C₁-C₆haloalkyl,C₁-C₆deuteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroarylis independently optionally substituted with one or more oxo, deuterium,halogen, —CN, —OH, —OMe, —NH₂, —C(═O)Me, —C(═O)OH, —C(═O)OMe,C₁-C₆alkyl, or C₁-C₆haloalkyl. In some embodiments of a compound ofFormula (XII), (XII′), (XIIa), or (XIIb), R⁸ is hydrogen, CN,C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, or cycloalkyl; whereineach alkyl, cycloalkyl, and heterocycloalkyl is independently optionallysubstituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe,—C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl.

In some embodiments of a compound of Formula (XII), (XII′), (XIIa), or(XIIb), R⁹ and R¹⁰ are independently hydrogen, C₁-C₆alkyl,C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, cycloalkyl, heterocycloalkyl, aryl,or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl,and heteroaryl is independently optionally substituted with one or moreoxo, deuterium, halogen, —CN, —OH, —OMe, —NH₂, —C(═O)Me, —C(═O)OH,—C(═O)OMe, C₁-C₆alkyl, C₁-C₆deuteroalkyl, C₁-C₆haloalkyl, orC₁-C₆hydroxyalkyl. In some embodiments of a compound of Formula (XII),(XII′), (XIIa), or (XIIb), R⁹ and R¹⁰ are independently hydrogen,C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, or cycloalkyl; whereineach alkyl, cycloalkyl, and heterocycloalkyl is independently optionallysubstituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe,—NH₂, —C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, C₁-C₆deuteroalkyl,C₁-C₆haloalkyl, or C₁-C₆hydroxyalkyl.

In some embodiments of a. compound of Formula (XII), (XII′), (XIIa), or(XIIb), R⁹ and R¹⁰ are taken together with the nitrogen atom to whichthey are attached to form a heterocycloalkyl optionally substituted withone or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH₂, —C(═O)Me,—C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl. In some embodimentsof a compound of Formula (XII), (XII′), (XIIa), or (XIIb), R⁹ and R¹⁰are taken together with the nitrogen atom to which they are attached toform a C₂-C₈heterocycloalkyl optionally substituted with one or moreoxo, deuterium, halogen, —CN, —OH, —OMe, —NH₂, —C(═O)Me, —C(═O)OH,—C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl. In some embodiments of acompound of Formula (XII), (XII′), (XIIa), or (XIIb), R⁹ and R¹⁰ aretaken together with the nitrogen atom to which they are attached to forma bicyclic heterocycloalkyl or a spiro heterocycloalkyl optionallysubstituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe,—NH₂, —C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl. Insome embodiments of a compound of Formula (XII), (XII′), (XIIa), or(XIIb), R⁹ and R¹⁰ are taken together with the nitrogen atom to whichthey are attached to form a heterocycloalkyl selected from aziridinyl,azetidinyl, pyrrolidinyl, piperidinyl, 2-azabicyclo[1.1.1]pentanyl, or2-azaspiro[3.3]heptanyl, each optionally substituted with one or moreoxo, deuterium, halogen, —CN, —OH, —OMe, —NH₂, —C(═O)Me, —C(═O)OH,—C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl.

In some embodiments of a compound of Formula (XII), the compound is ofFormula (XIIc):

wherein R^(5a) is deuterium, halogen, —CN, —OR^(b), —NR^(c)R^(d),—C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆alkyl,C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,C₁-C₆heteroalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl,heterocycloalkyl, aryl, heteroaryl, C₁-C₆alkyl(cycloalkyl),C₁-C₆alkyl(heterocycloalkyl), C₁-C₆alkyl(aryl), orC₁-C₆alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl,cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independentlyoptionally substituted with one or more oxo, deuterium, halogen, —CN,—OR^(b), —NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d),C₁-C₆alkyl, or C₁-C₆haloalkyl.

In some embodiments of a compound of Formula (XIIc); R^(5a) isdeuterium, halogen, —CN, —OR^(b), —NR^(c)R^(d), C₁-C₆alkyl,C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,C₁-C₆heteroalkyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl,heteroaryl, C₁-C₆alkyl(cycloalkyl), C₁-C₆alkyl(heterocycloalkyl),C₁-C₆alkyl(aryl), or C₁-C₆alkyl(heteroaryl); wherein each alkyl,alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl isindependently optionally substituted with one or more oxo, deuterium,halogen, —CN, —OR^(b), —NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b),—C(═O)NR^(c)R^(d), C₁-C₆alkyl, or C₁-C₆haloalkyl.

In some embodiments of a compound of Formula (XIIc); R^(5a) is halogen,—OR^(b), C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl,C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, C₂-C₆alkynyl,cycloalkyl, heterocycloalkyl, aryl, C₁-C₆alkyl(cycloalkyl), orC₁-C₆alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl,cycloalkyl, heterocycloalkyl, and aryl is independently optionallysubstituted with one or more oxo, deuterium, halogen, —CN, —OR^(b),—NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆alkyl,or C₁-C₆haloalkyl.

Also disclosed herein is a compound of Formula (XIII), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof:

wherein:

-   -   Ring B is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;    -   R³ is hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl, or        C₁-C₆deuteroalkyl;    -   R⁴ is hydrogen, deuterium, halogen, —CN, —OR^(b), —SR^(b),        —S(═O)R^(a), —S(═O)₂R^(a), —NO₂, —NR^(c)R^(d), —NHS(═O)₂R^(a),        —S(═O)₂NR^(c)R^(d), —C(═O)R^(a), —OC(═O)R^(a), —C(═O)OR^(b),        —OC(═O)OR^(b), —C(═O)NR^(c)R^(d), —OC(═O)NR^(c)R^(d),        —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a), —NR^(b)C(═O)OR^(b),        C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl,        C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₂-C₆alkenyl, or        C₂-C₆alkynyl;    -   or R³ and R⁴ are taken together to form an optionally        substituted ring;    -   L is a bond or —C(═O)—;    -   Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;        each optionally substituted with one or more R^(A);    -   each R^(A) is independently deuterium, halogen, —CN, —OR^(b),        —SR^(b), —S(═O)R^(a), —S(═O)₂R^(a), —NO₂, —NR^(c)R^(d),        —NHS(═O)₂R^(a), —S(═O)₂NR^(c)R^(d), —C(═O)R^(a), —OC(═O)R^(a),        —C(═O)OR^(b), —OC(═O)OR^(b), —C(═O)NR^(c)R^(d),        —OC(═O)NR^(c)R^(d), —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a),        —NR^(b)C(═O)OR^(b), C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,        C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl,        or heteroaryl; wherein each alkyl, alkenyl, alkenyl, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl is independently        optionally substituted with one or more oxo, deuterium, halogen,        —CN, —OR^(b), —NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b),        —C(═O)NR^(c)R^(d), C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   or two R^(A) on the same carbon are taken together to form an        oxo;    -   or -L-Ring A is absent;    -   each X is independently —CR^(x)— or —N—;    -   each R^(x) is independently hydrogen, deuterium, halogen, —CN,        —OR^(b), —SR^(b), —S(═O)R^(a), —S(═O)₂R^(a), —NO₂, —NR^(c)R^(d),        —NHS(═O)₂R^(a), —S(═O)₂NR^(c)R^(d), —C(═O)R^(a), —OC(═O)R^(a),        —C(═O)OR^(b), —OC(═O)OR^(b), —C(═O)NR^(c)R^(d),        —OC(═O)NR^(c)R^(d), —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a),        —NR^(b)C(═O)OR^(b), C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,        C₂-C₆alkenyl, or C₂-C₆alkynyl;    -   R⁵ is halogen, —CN, —OR⁸, —SR⁸, —S(═O)R⁷, —S(═O)₂R⁷, —NO₂,        —NR⁹R¹⁰, —NR⁸S(═O)R⁷, —NR⁸S(═O)₂R⁷, —S(═O)₂NR⁹R¹⁰, —C(═N—CN)R⁷,        —C(═O)R⁷, 13 OC(═N—CN)R⁷, —OC(—O)R⁷, —C(═N—CN)OR⁸, —C(═O)OR⁸,        —OC(═N—CN)OR⁸, —OC(═O)OR⁸, —C(═N—CN)NR⁹R¹⁰, —C(═O)NR⁹R¹⁰,        —OC(═N—CN)NR⁹R¹⁰, —OC(═O)NR⁹R¹⁰, —NR⁸C(═N—CN)NR⁹R¹⁰,        —NR⁸C(═O)NR⁹R¹⁰, —NR⁸C(═N—CN)R⁷, —NR⁸C(═N—OH)R⁷,        —NR⁸C(═N—CN)OR⁸, —NR⁸C(═O)OR⁸, —NR⁸S(═O)(═NR⁸)R⁷, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,        C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl,        alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one or        more oxo, deuterium, halogen, —CN, —OR^(b), —NR^(c)R^(d),        —C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,        C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,        cycloalkyl, heterocycloalkyl, aryl, heteroaryl,        C₁-C₆alkyl(cycloalkyl), C₁-C₆alkyl(heterocycloalkyl),        C₁-C₆alkyl(aryl), or C₁-C₆alkyl(heteroaryl); wherein each alkyl,        alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one or        more oxo, deuterium, halogen, —CN, —OR^(b), —NR^(c)R^(d),        —C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆alkyl, or        C₁-C₆haloalkyl;    -   or R^(x) and R⁵ are taken together to form ring D optionally        substituted with one or more R^(D);    -   Ring D is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;    -   each R^(D) is independently hydrogen, deuterium, halogen, —CN,        —OR^(b), —SR^(b), —S(═O)R^(a), —S(═O)₂R^(a), —NO₂, —NR^(c)R^(d),        —NHS(═O)₂R^(a), —S(═O)₂NR^(c)R^(d), —C(═O)R^(a), —OC(═O)R^(a),        —C(═O)OR^(b), —OC(═O)OR^(b), —C(═O)NR^(c)R^(d),        —OC(═O)NR^(c)R^(d), —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a),        —NR^(b)C(═O)OR^(b), C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,        C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl,        or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl is independently        optionally substituted with one or more oxo, deuterium, halogen,        —CN, —OR^(b), —NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b),        —C(═O)NR^(c)R^(d), C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   or two R^(D) on the same carbon are taken together to form an        oxo;    -   R⁷ is C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl,        C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,        cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each        alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one or        more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH₂, —C(═O)Me,        —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   each R⁸ is independently hydrogen, CN, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,        C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl,        alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one or        more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH₂, —C(═O)Me,        —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   R⁹ and R¹⁰ are independently hydrogen, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,        C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl,        alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one or        more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH₂, —C(═O)Me,        —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, C₁-C₆deuteroalkyl,        C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆hydroxydeuteroalkyl,        cycloalkyl, or heterocycloalkyl;    -   or R⁹ and R¹⁰ are taken together with the nitrogen atom to which        they are attached to form a heterocycloalkyl optionally        substituted with one or more oxo, deuterium, halogen, —CN, —OH,        —OMe, —NH₂, —C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or        C₁-C₆haloalkyl;    -   or R⁸ and R⁹ are taken together with the atoms to which they are        attached to form a heterocycloalkyl optionally substituted with        one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH₂,        —C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   R¹¹ is C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl,        C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,        cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each        alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one or        more R^(11a);    -   each R^(11a) is independently deuterium, halogen, —CN, —OR^(b),        —SR^(b), —S(═O)R^(a), —S(═O)₂R^(a), —NO₂, —NR^(c)R^(d),        —NHS(═O)₂R^(a), —S(═O)₂NR^(c)R^(d), —C(═O)R^(a), —OC(═O)R^(a),        —C(═O)OR^(b), —OC(═O)OR^(b), —C(═O)NR^(c)R^(d),        —OC(═O)NR^(c)R^(d), —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a),        —NR^(b)C(═O)OR^(b), C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,        C₂-C₆alkenyl, or C₂-C₆alkenyl;    -   each R^(a) is independently C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,        C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl,        or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl is independently        optionally substituted with one or more oxo, deuterium, halogen,        —CN, —OH, —OMe, —NH₂, —C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl,        or C₁-C₆haloalkyl;    -   each R^(b) is independently hydrogen, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,        C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl,        alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one or        more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH₂, —C(═O)Me,        —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   each R^(c) and R^(d) is independently hydrogen, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,        C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl,        alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one or        more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH₂, —C(═O)Me,        —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   or R^(c) and R^(d) are taken together with the nitrogen atom to        which they are attached to form a heterocycloalkyl optionally        substituted with one or more oxo, deuterium, halogen, —CN, —OH,        —OMe, —NH₂, —C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or        C₁-C₆haloalkyl.

Also disclosed herein is a compound of Formula (XIII), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof:

wherein:

-   -   Ring B is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;    -   R³ is hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl, or        C₁-C₆deuteroalkyl;    -   R⁴ is hydrogen, deuterium, halogen, —CN, —OR^(b), —SR^(b),        —S(═O)R^(a), —S(═O)₂R^(a), —NO₂, —NR^(c)R^(d), —NHS(═O)₂R^(a),        —S(═O)₂NR^(c)R^(d), —C(═O)R^(a), —OC(═O)R^(a), —C(═O)OR^(b),        —OC(═O)OR^(b), —C(═O)NR^(c)R^(d), —OC(═O)NR^(c)R^(d),        —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a), —NR^(b)C(═O)OR^(b),        C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl,        C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₂-C₆alkenyl, or        C₂-C₆alkynyl;    -   or R³ and R⁴ are taken together to form an optionally        substituted ring;    -   L is a bond or —C(═O)—;    -   Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;        each optionally substituted with one or more R^(A);    -   each R^(A) is independently deuterium, halogen, —CN, —OR^(b),        —SR^(b), —S(═O)R^(a), —S(═O)₂R^(a), —NO₂, —NR^(c)R^(d),        —NHS(═O)₂R^(a), —S(═O)₂NR^(c)R^(d), —C(═O)R^(a), —OC(═O)R^(a),        —C(═O)OR^(b), —OC(═O)OR^(b), —C(═O)NR^(c)R^(d),        —OC(═O)NR^(c)R^(d), —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a),        —NR^(b)C(═O)OR^(b), C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,        C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl,        or heteroaryl; wherein each alkyl, alkenyl, alkenyl, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl is independently        optionally substituted with one or more oxo, deuterium, halogen,        —CN, —OR^(b), —NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b),        —C(═O)NR^(c)R^(d), C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   or two R^(A) on the same carbon are taken together to form an        oxo;    -   each X is independently —CR^(x)— or —N—;    -   each R^(x) is independently hydrogen, deuterium, halogen, —CN,        —OR^(b), —SR^(b), —S(═O)R^(a), —S(═O)₂R^(a), —NO₂, —NR^(c)R^(d),        —NHS(═O)₂R^(a), —S(═O)₂NR^(c)R^(d), —C(═O)R^(a), —OC(═O)R^(a),        —C(═O)OR^(b), —OC(═O)OR^(b), —C(═O)NR^(c)R^(d),        —OC(═O)NR^(c)R^(d), —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a),        —NR^(b)C(═O)OR^(b), C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,        C₂-C₆alkenyl, or C₂-C₆alkynyl;    -   R⁵ is halogen, —CN, —OR⁸, —SR⁸, —S(═O)R⁷, —S(═O)₂R⁷, —NO₂,        —NR⁹R¹⁰, —NR⁸S(═O)R⁷, —NR⁸S(═O)₂R⁷, —S(═O)₂NR⁹R¹⁰, —C(═N—CN)R⁷,        —C(═O)R⁷, 13 OC(═N—CN)R⁷, —OC(—O)R⁷, —C(═N—CN)OR⁸, —C(═O)OR⁸,        —OC(═N—CN)OR⁸, —OC(═O)OR⁸, —C(═N—CN)NR⁹R¹⁰, —C(═O)NR⁹R¹⁰,        —OC(═N—CN)NR⁹R¹⁰, —OC(═O)NR⁹R¹⁰, —NR⁸C(═N—CN)NR⁹R¹⁰,        —NR⁸C(═O)NR⁹R¹⁰, —NR⁸C(═N—CN)R⁷, —NR⁸C(═N—OH)R⁷,        —NR⁸C(═N—CN)OR⁸, —NR⁸C(═O)OR⁸, —NR⁸S(═O)(═NR⁸)R⁷, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,        C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl,        alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one or        more oxo, deuterium, halogen, —CN, —OR^(b), —NR^(c)R^(d),        —C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,        C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,        cycloalkyl, heterocycloalkyl, aryl, heteroaryl,        C₁-C₆alkyl(cycloalkyl), C₁-C₆alkyl(heterocycloalkyl),        C₁-C₆alkyl(aryl), or C₁-C₆alkyl(heteroaryl); wherein each alkyl,        alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one or        more oxo, deuterium, halogen, —CN, —OR^(b), —NR^(c)R^(d),        —C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆alkyl, or        C₁-C₆haloalkyl;    -   or R^(x) and R⁵ are taken together to form ring D optionally        substituted with one or more R^(D);    -   Ring D is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;    -   each R^(D) is independently hydrogen, deuterium, halogen, —CN,        —OR^(b), —SR^(b), —S(═O)R^(a), —S(═O)₂R^(a), —NO₂, —NR^(c)R^(d),        —NHS(═O)₂R^(a), —S(═O)₂NR^(c)R^(d), —C(═O)R^(a), —OC(═O)R^(a),        —C(═O)OR^(b), —OC(═O)OR^(b), —C(═O)NR^(c)R^(d),        —OC(═O)NR^(c)R^(d), —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a),        —NR^(b)C(═O)OR^(b), C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,        C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl,        or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl is independently        optionally substituted with one or more oxo, deuterium, halogen,        —CN, —OR^(b), —NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b),        —C(═O)NR^(c)R^(d), C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   or two R^(D) on the same carbon are taken together to form an        oxo;    -   R⁷ is C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl,        C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,        cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each        alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one or        more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH₂, —C(═O)Me,        —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   each R⁸ is independently hydrogen, CN, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,        C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl,        alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one or        more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH₂, —C(═O)Me,        —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   R⁹ and R¹⁰ are independently hydrogen, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,        C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl,        alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one or        more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH₂, —C(═O)Me,        —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, C₁-C₆deuteroalkyl,        C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆hydroxydeuteroalkyl,        cycloalkyl, or heterocycloalkyl;    -   or R⁹ and R¹⁰ are taken together with the nitrogen atom to which        they are attached to form a heterocycloalkyl optionally        substituted with one or more oxo, deuterium, halogen, —CN, —OH,        —OMe, —NH₂, —C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or        C₁-C₆haloalkyl;    -   or R⁸ and R⁹ are taken together with the atoms to which they are        attached to form a heterocycloalkyl optionally substituted with        one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH₂,        —C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   R¹¹ is C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl,        C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,        cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each        alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one or        more R^(11a);    -   each R^(11a) is independently deuterium, halogen, —CN, —OR^(b),        —SR^(b), —S(═O)R^(a), —S(═O)₂R^(a), —NO₂, —NR^(c)R^(d),        —NHS(═O)₂R^(a), —S(═O)₂NR^(c)R^(d), —C(═O)R^(a), —OC(═O)R^(a),        —C(═O)OR^(b), —OC(═O)OR^(b), —C(═O)NR^(c)R^(d),        —OC(═O)NR^(c)R^(d), —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a),        —NR^(b)C(═O)OR^(b), C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,        C₂-C₆alkenyl, or C₂-C₆alkenyl;    -   each R^(a) is independently C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,        C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl,        or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl is independently        optionally substituted with one or more oxo, deuterium, halogen,        —CN, —OH, —OMe, —NH₂, —C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl,        or C₁-C₆haloalkyl;    -   each R^(b) is independently hydrogen, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,        C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl,        alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one or        more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH₂, —C(═O)Me,        —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   each R^(c) and R^(d) is independently hydrogen, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,        C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl,        alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one or        more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH₂, —C(═O)Me,        —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   or R^(c) and R^(d) are taken together with the nitrogen atom to        which they are attached to form a heterocycloalkyl optionally        substituted with one or more oxo, deuterium, halogen, —CN, —OH,        —OMe, —NH₂, —C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or        C₁-C₆haloalkyl.

Also disclosed herein is a compound of Formula (XIII), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof:

wherein:

-   -   Ring B is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;    -   R³ is hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl, or        C₁-C₆deuteroalkyl;    -   R⁴ is hydrogen, deuterium, halogen, —CN, —OR^(b), —SR^(b),        —S(═O)R^(a), —S(═O)₂R^(a), —NO₂, —NR^(c)R^(d), —NHS(═O)₂R^(a),        —S(═O)₂NR^(c)R^(d), —C(═O)R^(a), —OC(═O)R^(a), —C(═O)OR^(b),        —OC(═O)OR^(b), —C(═O)NR^(c)R^(d), —OC(═O)NR^(c)R^(d),        —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a), —NR^(b)C(═O)OR^(b),        C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl,        C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₂-C₆alkenyl, or        C₂-C₆alkynyl;    -   or R³ and R⁴ are taken together to form an optionally        substituted ring;    -   each X is independently —CR^(x)— or —N—;    -   each R^(x) is independently hydrogen, deuterium, halogen, —CN,        —OR^(b), —SR^(b), —S(═O)R^(a), —S(═O)₂R^(a), —NO₂, —NR^(c)R^(d),        —NHS(═O)₂R^(a), —S(═O)₂NR^(c)R^(d), —C(═O)R^(a), —OC(═O)R^(a),        —C(═O)OR^(b), —OC(═O)OR^(b), —C(═O)NR^(c)R^(d),        —OC(═O)NR^(c)R^(d), —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a),        —NR^(b)C(═O)OR^(b), C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,        C₂-C₆alkenyl, or C₂-C₆alkynyl;    -   R⁵ is halogen, —CN, —OR⁸, —SR⁸, —S(═O)R⁷, —S(═O)₂R⁷, —NO₂,        —NR⁹R¹⁰, —NR⁸S(═O)R⁷, —NR⁸S(═O)₂R⁷, —S(═O)₂NR⁹R¹⁰, —C(═N—CN)R⁷,        —C(═O)R⁷, 13 OC(═N—CN)R⁷, —OC(—O)R⁷, —C(═N—CN)OR⁸, —C(═O)OR⁸,        —OC(═N—CN)OR⁸, —OC(═O)OR⁸, —C(═N—CN)NR⁹R¹⁰, —C(═O)NR⁹R¹⁰,        —OC(═N—CN)NR⁹R¹⁰, —OC(═O)NR⁹R¹⁰, —NR⁸C(═N—CN)NR⁹R¹⁰,        —NR⁸C(═O)NR⁹R¹⁰, —NR⁸C(═N—CN)R⁷, —NR⁸C(═N—OH)R⁷,        —NR⁸C(═N—CN)OR⁸, —NR⁸C(═O)OR⁸, —NR⁸S(═O)(═NR⁸)R⁷, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,        C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl,        alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one or        more oxo, deuterium, halogen, —CN, —OR^(b), —NR^(c)R^(d),        —C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,        C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,        cycloalkyl, heterocycloalkyl, aryl, heteroaryl,        C₁-C₆alkyl(cycloalkyl), C₁-C₆alkyl(heterocycloalkyl),        C₁-C₆alkyl(aryl), or C₁-C₆alkyl(heteroaryl); wherein each alkyl,        alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one or        more oxo, deuterium, halogen, —CN, —OR^(b), —NR^(c)R^(d),        —C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆alkyl, or        C₁-C₆haloalkyl;    -   or R^(x) and R⁵ are taken together to form ring D optionally        substituted with one or more R^(D);    -   Ring D is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;    -   each R^(D) is independently hydrogen, deuterium, halogen, —CN,        —OR^(b), —SR^(b), —S(═O)R^(a), —S(═O)₂R^(a), —NO₂, —NR^(c)R^(d),        —NHS(═O)₂R^(a), —S(═O)₂NR^(c)R^(d), —C(═O)R^(a), —OC(═O)R^(a),        —C(═O)OR^(b), —OC(═O)OR^(b), —C(═O)NR^(c)R^(d),        —OC(═O)NR^(c)R^(d), —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a),        —NR^(b)C(═O)OR^(b), C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,        C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl,        or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl is independently        optionally substituted with one or more oxo, deuterium, halogen,        —CN, —OR^(b), —NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b),        —C(═O)NR^(c)R^(d), C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   or two R^(D) on the same carbon are taken together to form an        oxo;    -   R⁷ is C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl,        C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,        cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each        alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one or        more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH₂, —C(═O)Me,        —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   each R⁸ is independently hydrogen, CN, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,        C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl,        alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one or        more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH₂, —C(═O)Me,        —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   R⁹ and R¹⁰ are independently hydrogen, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,        C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl,        alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one or        more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH₂, —C(═O)Me,        —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, C₁-C₆deuteroalkyl,        C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆hydroxydeuteroalkyl,        cycloalkyl, or heterocycloalkyl;    -   or R⁹ and R¹⁰ are taken together with the nitrogen atom to which        they are attached to form a heterocycloalkyl optionally        substituted with one or more oxo, deuterium, halogen, —CN, —OH,        —OMe, —NH₂, —C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or        C₁-C₆haloalkyl;    -   or R⁸ and R⁹ are taken together with the atoms to which they are        attached to form a heterocycloalkyl optionally substituted with        one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH₂,        —C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   R¹¹ is C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl,        C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,        cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each        alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one or        more R^(11a);    -   each R^(11a) is independently deuterium, halogen, —CN, —OR^(b),        —SR^(b), —S(═O)R^(a), —S(═O)₂R^(a), —NO₂, —NR^(c)R^(d),        —NHS(═O)₂R^(a), —S(═O)₂NR^(c)R^(d), —C(═O)R^(a), —OC(═O)R^(a),        —C(═O)OR^(b), —OC(═O)OR^(b), —C(═O)NR^(c)R^(d),        —OC(═O)NR^(c)R^(d), —NR^(b)C(═O)NR^(c)R^(d), —NR^(b)C(═O)R^(a),        —NR^(b)C(═O)OR^(b), C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,        C₂-C₆alkenyl, or C₂-C₆alkenyl;    -   each R^(a) is independently C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,        C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl,        or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl is independently        optionally substituted with one or more oxo, deuterium, halogen,        —CN, —OH, —OMe, —NH₂, —C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl,        or C₁-C₆haloalkyl;    -   each R^(b) is independently hydrogen, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,        C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl,        alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one or        more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH₂, —C(═O)Me,        —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   each R^(c) and R^(d) is independently hydrogen, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,        C₁-C₆aminoalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl,        alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is independently optionally substituted with one or        more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH₂, —C(═O)Me,        —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl;    -   or R^(c) and R^(d) are taken together with the nitrogen atom to        which they are attached to form a heterocycloalkyl optionally        substituted with one or more oxo, deuterium, halogen, —CN, —OH,        —OMe, —NH₂, —C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or        C₁-C₆haloalkyl.

In some embodiments of a compound of Formula (XIII), Ring B is aryl orheteroaryl. In some embodiments of a compound of Formula (XIII), Ring Bis aryl. In some embodiments of a compound of Formula (XIII), Ring B isphenyl. In some embodiments of a compound of Formula (XIII), Ring B isheteroaryl. In some embodiments of a compound of Formula (XIII), Ring Bis 5- or 6-membered heteroaryl. In some embodiments of a compound ofFormula (XIII), Ring B is 6-membered heteroaryl. In some embodiments ofa compound of Formula (XIII), Ring B is 6-membered pyridyl.

In some embodiments of a compound of Formula (XIII), L is a bond. Insome embodiments of a compound of Formula (XIII), L is —C(═O)—.

In some embodiments of a compound of Formula (XIII), L-Ring A is absent.

In some embodiments of a compound of Formula (XIII), Ring A isheterocycloalkyl or heteroaryl; each optionally substituted with one ormore R^(A). In some embodiments of a compound of Formula (XIII), Ring Ais a 5-membered heterocycloalkyl or a 5-membered heteroaryl; eachoptionally substituted with one or more R^(A). In some embodiments of acompound of Formula (XIII), Ring A is heteroaryl optionally substitutedwith one or more R^(A).

In some embodiments of a compound of Formula (XIII), each R^(A) isindependently deuterium, halogen, —CN, —OR^(b), —NR^(c)R^(d),—C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d), —OC(═O)NR^(c)R^(d),C₁-C₆alkyl, C₁-C₆haloalkyl, or C₁-C₆deuteroalkyl. In some embodiments ofa compound of Formula (XIII), each R^(A) is independently deuterium,halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, or C₁-C₆deuteroalkyl. In someembodiments of a compound of Formula (XIII), each R^(A) is independentlyC₁-C₆alkyl.

In some embodiments of a compound of Formula (XIII), the compound is ofFormula (XIIIa):

In some embodiments of a compound of Formula (XIII), the compound is ofFormula (XIIIb):

In some embodiments of a compound of Formula (XIII), the compound is ofFormula (XIIIc):

In some embodiments of a compound of Formula (XIII), the compound is ofFormula (XIIId):

In some embodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId),R⁴ is hydrogen, deuterium, halogen, —CN, —OR^(b), —S(═O)₂R^(a),—NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆alkyl,C₁-C₆haloalkyl, or C₁-C₆deuteroalkyl. In some embodiments of a compoundof Formula (XIII) or (XIIIa)-(XIIId), R⁴ is hydrogen, deuterium,halogen, —CN, —OR^(b), —NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b),—C(═O)NR^(c)R^(d), —OC(═O)NR^(c)R^(d), C₁-C₆alkyl, C₁-C₆haloalkyl, orC₁-C₆deuteroalkyl. In some embodiments of a compound of Formula (XIII)or (XIIIa)-(XIIId), R⁴ is hydrogen or —OR^(b). In some embodiments of acompound of Formula (XIII) or (XIIIa)-(XIIId), R⁴ is —OR^(b). In someembodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId), R⁴ ishydrogen. In some embodiments of a. compound of Formula (XIII) or(XIIIa)-(XIIId), R⁴ is —P(═O)R^(b)R^(b). In some embodiments of acompound of Formula (XIII) or (XIIIa)-(XIIId), R⁴ is —S(═O)₂R^(b).

In some embodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId),each X is —N—. In some embodiments of a compound of Formula (XIII) or(XIIIa)-(XIIId) each X is —CR^(X)—. In some embodiments of a compound ofFormula (XIII) or (XIIIa)-(XIIId), two X are —N— and the other is—CR^(X)—. In some embodiments of a compound of Formula (XIII) or(XIIIa)-(XIIId), one X is —N— and the others are —CR^(X)—. In someembodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId), each Xis —CH—. In some embodiments of a compound of Formula (XIII) or(XIIIa)-(XIIId), two X are —N— and the other is —CH—. In someembodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId), one X is—N— and the others are —CH—. In some embodiments of a compound ofFormula (XIII) or (XIIIa)-(XIIId),

is

In some embodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId),

is

In some embodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId),

is

In some embodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId),each R^(X) is independently hydrogen, deuterium, halogen, —CN, —OR^(b),—NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b), C₁-C₆alkyl, C₁-C₆haloalkyl,C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, or C₁-C₆aminoalkyl. In someembodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId), eachR^(X) is independently hydrogen, deuterium, halogen, C₁-C₆alkyl,C₁-C₆haloalkyl, or C₁-C₆deuteroalkyl. In some embodiments of a compoundof Formula (XIII) or (XIIIa)-(XIIId), each R^(X) is independentlyhydrogen, deuterium, or halogen.

In some embodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId),

is

In some embodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId),

is

In some embodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId),

is

In some embodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId),R³ is hydrogen or C₁-C₆alkyl. In some embodiments of a compound ofFormula (XIII) or (XIIIa)-(XIIId), R³ is hydrogen.

In some embodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId),R¹¹ is C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,C₁-C₆aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroarylis independently optionally substituted with one or more R^(11a). Insome embodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId), R¹¹is C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl,C₁-C₆aminoalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl,cycloalkyl, and heterocycloalkyl is independently optionally substitutedwith one or more R^(11a). In some embodiments of a compound of Formula(XIII) or (XIIIa)-(XIIId), R¹¹ is C₁-C₆alkyl, C₁-C₆haloalkyl,C₁-C₆deuteroalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl,cycloalkyl, and heterocycloalkyl is independently optionally substitutedwith one or more R^(11a). In some embodiments of a compound of Formula(XIII) or (XIIIa)-(XIIId), R¹¹ is C₁-C₆alkyl, C₁-C₆haloalkyl, orcycloalkyl; wherein each alkyl and cycloalkyl is independentlyoptionally substituted with one or more R^(11a). In some embodiments ofa compound of Formula (XIII) or (XIIIa)-(XIIId), R¹¹ is C₁-C₆alkyl orcycloalkyl; wherein each alkyl and cycloalkyl is independentlyoptionally substituted with one or more R^(11a). In some embodiments ofa compound of Formula (XIII) or (XIIIa)-(XIIId), R¹¹ is C₁-C₆alkyl,C₁-C₆deuteroalkyl, C₁-C₆haloalkyl, or cycloalkyl. In some embodiments ofa compound of Formula (XIII) or (XIIIa)-(XIIId), R¹¹ is C₁-C₆alkyl,C₁-C₆haloalkyl, or cycloalkyl. In some embodiments of a compound ofFormula (XIII) or (XIIIa)-(XIIId), R¹¹ is C₁-C₆deuteroalkyl. In someembodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId), R¹¹C₁-C₆alkyl. In some embodiments of a compound of Formula (XIII) or(XIIIa)-(XIIId), R¹¹ is cycloalkyl.

In some embodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId),each R^(11a) is independently deuterium, halogen, —CN, —OR^(b),—NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆alkyl,C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, orC₁-C₆aminoalkyl. In some embodiments of a compound of Formula (XIII) or(XIIIa)-(XIIId), each R^(11a) is independently deuterium, halogen, —CN,—OR^(b), —NR^(c)R^(d), C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl,C₁-C₆hydroxyalkyl, or C₁-C₆aminoalkyl. In some embodiments of a compoundof Formula (XIII) or (XIIIa)-(XIIId), each R^(11a) is independentlydeuterium, halogen, —CN, —OR^(b), —NR^(c)R^(d), C₁-C₆alkyl,C₁-C₆haloalkyl, or C₁-C₆deuteroalkyl. In some embodiments of a compoundof Formula (XIII) or (XIIIa)-(XIIId), each R^(11a) is independentlydeuterium, halogen, —CN, —OR^(b), —NR^(c)R^(d), or C₁-C₆alkyl. In someembodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId), eachR^(11a) is independently deuterium, halogen, C₁-C₆alkyl, C₁-C₆haloalkyl,or C₁-C₆deuteroalkyl. In some embodiments of a compound of Formula(XIII) or (XIIIa)-(XIIId), each R^(11a) is independently deuterium,halogen, or C₁-C₆alkyl.

In some embodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId),R⁵ is halogen, —CN, —OR⁸, —NR⁹R¹⁰, —C(═O)R⁷, —C(═O)OR⁸, —C(═O)NR⁹R¹⁰,—NR⁸C(═O)NR⁹R¹⁰, —NR⁸C(═N—CN)R⁷, —NR⁸C(═O)R⁷, —NR⁸C(═O)OR⁸,—NR⁸S(═O)(═NR⁸)R⁷, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl,C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl, orheteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, andheteroaryl is independently optionally substituted with one or more oxo,deuterium, halogen, —CN, —OR^(b), —NR^(c)R^(d), —C(═O)R^(a),—C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆alkyl, or C₁-C₆haloalkyl.

In some embodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId),R⁵ is halogen, —CN, —OR⁸, —NR⁹R¹⁰, —C(═O)R⁷, —C(═O)OR⁸, —C(═O)NR⁹R¹⁰,—NR⁸C(═O)NR⁹R¹⁰, —NR⁸C(═N—CN)R⁷, —NR⁸C(═O)OR⁸, —NR⁸S(═O)(═NR⁸)R⁷,C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₂-C₆alkenyl,C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; whereineach alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl isindependently optionally substituted with one or more oxo, deuterium,halogen, —CN, —OR^(b), —NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b),—C(═O)NR^(c)R^(d), C₁-C₆alkyl, or C₁-C₆haloalkyl.

In some embodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId),R⁵ is halogen, —CN, —OR⁸, —NR⁹R¹⁰, —C(═O)R⁷, —C(═O)OR⁸, —C(═O)NR⁹R¹⁰,—NR⁸C(═O)NR⁹R¹⁰, —NR⁸C(═N—CN)R⁷, —NR⁸C(═O)OR⁸, —NR⁸S(═O)(═NR⁸)R⁷,C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₂-C₆alkenyl,C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; whereineach alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl isindependently optionally substituted with one or more oxo, deuterium,halogen, —CN, —OR^(b), —NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b),—C(═O)NR^(c)R^(d), C₁-C₆alkyl, or C₁-C₆haloalkyl.

In some embodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId),R⁵ is —OR⁸, —NR⁹R¹⁰, —C(═O)R⁷, —C(═O)OR⁸, —C(═O)NR⁹R¹⁰, —NR⁸C(═O)NR⁹R¹⁰,—NR⁸C(═N—CN)R⁷, —NR⁸C(═O)R⁷, —NR⁸C(═O)OR⁸, —NR⁸S(═O)(═NR⁸)R⁷,cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein eachcycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independentlyoptionally substituted with one or more oxo, deuterium, halogen, —CN,—OR^(b), —NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d),C₁-C₆alkyl, or C₁-C₆haloalkyl.

In some embodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId),R⁵ is —OR⁸, —NR⁹R¹⁰, —C(═O)R⁷, —C(═O)OR⁸, —C(═O)NR⁹R¹⁰, —NR⁸C(═O)NR⁹R¹⁰,—NR⁸C(═N—CN)R⁷, —NR⁸C(═O)OR⁸, —NR⁸S(═O)(═NR⁸)R⁷, cycloalkyl,heterocycloalkyl, aryl, or heteroaryl; wherein each cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is independently optionallysubstituted with one or more oxo, deuterium, halogen, —CN, —OR^(b),—NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆alkyl,or C₁-C₆haloalkyl. In some embodiments of a compound of Formula (XIII)or (XIIIa)-(XIIId), R⁵ is —OR⁸, —NR⁸C(═O)R⁷, —NR⁸C(═N—CN)R⁷,—NR⁸S(═O)(═NR⁸)R⁷, or aryl optionally substituted with one or moredeuterium, halogen, —CN, —OR^(b), —NR^(c)R^(d), —C(═O)R^(a),—C(═O)OR^(b), —C(50 O)NR^(c)R^(d), C₁-C₆alkyl, or C₁-C₆haloalkyl.

In some embodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId),R⁵ is —OR⁸, —NR⁹R¹⁰, —NR⁸C(═N—CN)R⁷, —NR⁸S(═O)(═NR⁸)R⁷, or aryloptionally substituted with one or more deuterium, halogen, —CN,—OR^(b), —NR^(c)R^(d), —C(═O)OR^(a), —C(═O)NR^(c)R^(d), C₁-C₆alkyl, orC₁-C₆haloalkyl.

In some embodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId),R⁵ is —OR⁸, —NR⁹R¹⁰, —NR⁸C(═O)R⁷, cycloalkyl, heterocycloalkyl, aryl, orheteroaryl; wherein each cycloalkyl, heterocycloalkyl, aryl, andheteroaryl is independently optionally substituted with one or more oxo,deuterium, halogen, —CN, —OR^(b), —NR^(c)R^(d), —C(═O)R^(a),—C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆alkyl, or C₁-C₆haloalkyl. In someembodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId), R⁵ is—NR⁸C(═O)R⁷. In some embodiments of a compound of Formula (XIII) or(XIIIa)-(XIIId), R⁵ is aryl optionally substituted with one or more oxo,deuterium, halogen, —CN, —OR^(b), —NR^(c)R^(d), —C(═O)R^(a),—C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆alkyl, or C₁-C₆haloalkyl.

In some embodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId),R⁵ is —NR⁹R¹⁰, —NR⁸C(═O)NR⁹R¹⁰, or —NR⁸C(═N—CN)R⁷.

In some embodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId),R⁵ is —NR⁹R¹⁰.

In some embodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId),R⁵ is —NR⁹R¹⁰ or —NR⁸C(═O)NR⁹R¹⁰.

In some embodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId),R⁵ is —NR⁸C(═N—CN)R⁷.

In some embodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId),R⁵ is —NR⁸S(═O)(═NR⁸)R⁷.

In some embodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId),R⁵ is —NR⁸C(═O)NR⁹R¹⁰ or —NR⁸C(═O)R⁷.

In some embodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId),R⁵ is —NR⁸C(═O)NR⁹R¹⁰.

In some embodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId),R⁵ is —NR⁸C(═O)R⁷.

In some embodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId),R⁵ is —NR⁸C(═O)NR⁹R¹⁰ or heterocycloalkyl optionally substituted withone or more oxo, deuterium, halogen, —CN, OR^(b), —NR^(c)R^(d),—C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆alkyl,C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,C₁-C₆heteroalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl,heterocycloalkyl, aryl, heteroaryl, C₁-C₆alkyl(cycloalkyl),C₁-C₆alkyl(heterocycloalkyl), C₁-C₆alkyl(aryl), orC₁-C₆alkyl(heteroaryl); wherein each alkyl, alkenyl, alkynyl,cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independentlyoptionally substituted with one or more oxo, deuterium, halogen, —CN,—OR^(b), —C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆alkyl, orC₁-C₆haloalkyl.

In some embodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId),R⁵ is heterocycloalkyl optionally substituted with one or more oxo,deuterium, halogen, —CN, —OR^(b), —NR^(c)R^(d), —C(═O)R^(a),—C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆alkyl, C₁-C₆haloalkyl,C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₁-C₆heteroalkyl,C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl, heterocycloalkyl, aryl,heteroaryl, C₁-C₆alkyl(cycloalkyl), C₁-C₆alkyl(heterocycloalkyl),C₁-C₆alkyl(aryl), C₁-C₆alkyl(heteroaryl), wherein each alkyl, alkenyl,alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl isindependently optionally substituted with one or more oxo, deuterium,halogen, —CN, —OR^(b), —NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b),—C(═O)NR^(c)R^(d), C₁-C₆alkyl, or C₁-C₆haloalkyl.

In some embodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId),R⁵ is heterocycloalkyl optionally substituted with one or more oxo,deuterium, halogen, —CN, —OR^(b), —NR^(c)R^(d), C₁-C₆alkyl,C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl,C₁-C₆heteroalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, cycloalkyl,heterocycloalkyl, aryl, heteroaryl, C₁-C₆alkyl(cycloalkyl), orC₁-C₆alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl,cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independentlyoptionally substituted with one or more oxo, deuterium, halogen, —CN,—OR^(b), —NR^(c)R^(d), —C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d),C₁-C₆alkyl, or C₁-C₆haloalkyl.

In some embodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId),R⁵ is heterocycloalkyl optionally substituted with one or more oxo,halogen, —OR^(b), C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl,C₁-C₆hydroxyalkyl, C₁-C₆aminoalkyl, C₁-C₆heteroalkyl, C₂-C₆alkynyl,cycloalkyl, heterocycloalkyl, aryl, C₁-C₆alkyl(cycloalkyl), orC₁-C₆alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, cycloalkyl,heterocycloalkyl, and aryl is independently optionally substituted withone or more oxo, deuterium, halogen, —CN, —OR^(b), —NR^(c)R^(d),—C(═O)R^(a), —C(═O)OR^(b), —C(═O)NR^(c)R^(d), C₁-C₆alkyl, orC₁-C₆haloalkyl.

In some embodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId),the heterocycloalkyl of R⁵ is

In some embodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId),the heterocycloalkyl of R⁵ is

In some embodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId),R⁷ is C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, cycloalkylheterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is independently optionallysubstituted with one or more oxo, deuterium, halogen, —CN, —OH, —OMe,—NH₂, —C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl. Insome embodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId), R⁷is C₁-C₆alkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl,cycloalkyl, or heterocycloalkyl is independently optionally substitutedwith one or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH₂,—C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl. In someembodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId), R⁷ isC₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, or cycloalkyl; whereineach alkyl and cycloalkyl is independently optionally substituted withone or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH₂, —C(═O)Me,—C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl. In some embodimentsof a compound of Formula (XIII) or (XIIIa)-(XIIId), R⁷ is C₁-C₆alkyl orcycloalkyl, wherein each alkyl and cycloalkyl is independentlyoptionally substituted with one or more oxo, deuterium, halogen, —CN,—OH, —OMe, —NH₂, —C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, orC₁-C₆haloalkyl. In some embodiments of a compound of Formula (XIII) or(XIIIa)-(XIIId), R⁷ is cycloalkyl optionally substituted with one ormore oxo, deuterium, halogen, —CN, —OH, —OMe, —NH₂, —C(═O)Me, —C(═O)OH,—C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl. In some embodiments of acompound of Formula (XIII) or (XIIIa)-(XIIId), R⁷ is unsubstitutedcycloalkyl. In some embodiments of a compound of Formula (XIII) or(XIIIa)-(XIIId), R⁷ is heterocycloalkyl optionally substituted with oneor more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH₂, —C(═O)Me,—C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl. In some embodimentsof a compound of Formula (XIII) or (XIIIa)-(XIIId), R⁷ is unsubstitutedheterocycloalkyl.

In some embodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId),R⁸ is hydrogen, CN, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl,cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl,cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independentlyoptionally substituted with one or more oxo, deuterium, halogen, —CN,—OH, —OMe, —NH₂, —C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, orC₁-C₆haloalkyl. In some embodiments of a compound of Formula (XIII) or(XIIIa)-(XIIId), R⁸ is hydrogen, CN, C₁-C₆alkyl, C₁-C₆haloalkyl,C₁-C₆deuteroalkyl, or cycloalkyl; wherein each alkyl, cycloalkyl, andheterocycloalkyl is independently optionally substituted with one ormore oxo, deuterium, halogen, —CN, —OH, —OMe, —NH₂, —C(═O)Me, —C(═O)OH,—C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl.

In some embodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId),R⁹ and R¹⁰ are independently hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl,C₁-C₆deuteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroarylis independently optionally substituted with one or more oxo, deuterium,halogen, —CN, —OH, —OMe, —C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl,C₁-C₆deuteroalkyl, C₁-C₆haloalkyl, or C₁-C₆hydroxyalkyl. In someembodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId), R⁹ andR¹⁰ are independently hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl,C₁-C₆deuteroalkyl, or cycloalkyl; wherein each alkyl, cycloalkyl, andheterocycloalkyl is independently optionally substituted with one ormore oxo, deuterium, halogen, —CN, —OH, —OMe, —NH₂, —C(═O)Me, —C(═O)OH,—C(═O)OMe, C₁-C₆alkyl, C₁-C₆deuteroalkyl, C₁-C₆haloalkyl, orC₁-C₆hydroxyalkyl.

In some embodiments of a compound of Formula (XIII) or (XIIIa)-(XIIId),R⁹ and R¹⁰ are taken together with the nitrogen atom to which they areattached to form a heterocycloalkyl optionally substituted with one ormore oxo, deuterium, halogen, —CN, —OH, —OMe, —NH₂, —C(═O)Me, —C(═O)OH,—C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl. In some embodiments of acompound of Formula (XIII) or (XIIIa)-(XIIId), R⁹ and R¹⁰ are takentogether with the nitrogen atom to which they are attached to form aC₂-C₆heterocycloalkyl optionally substituted with one or more oxo,deuterium, halogen, —CN, —OH, —OMe, —NH₂, —C(═O)Me, —C(═O)OH, —C(═O)OMe,C₁-C₆alkyl, or C₁-C₆haloalkyl. In some embodiments of a compound ofFormula (XIII) or (XIIIa)-(XIIId), R⁹ and R¹⁰ are taken together withthe nitrogen atom to which they are attached to form a bicyclicheterocycloalkyl or a spiro heterocycloalkyl optionally substituted withone or more oxo, deuterium, halogen, —CN, —OH, —OMe, —NH₂, —C(═O)Me,—C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, or C₁-C₆haloalkyl. In some embodimentsof a compound of Formula (XIII) or (XIIIa)-(XIIId), R⁹ and R¹⁰ are takentogether with the nitrogen atom to which they are attached to form aheterocycloalkyl selected from aziridinyl, azetidinyl, pyrrolidinyl,piperidinyl, 2-azabicyclo[1.1.1]pentanyl, or 2-azaspiro[3.3]heptanyl,each optionally substituted with one or more oxo, deuterium, halogen,—CN, —OH, —OMe, —NH₂, —C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, orC₁-C₆haloalkyl.

In some embodiments of a compound described above, each R^(a) isindependently C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl, orcycloalkyl; wherein each alkyl and cycloalkyl is independentlyoptionally substituted with one or more oxo, deuterium, halogen, —CN,—OH, —OMe, —NH₂, —C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, orC₁-C₆haloalkyl. In some embodiments of a compound described above, eachis independently C₁-C₆alkyl, C₁-C₆haloalkyl, or C₁-C₆deuteroalkyl. Insome embodiments of a compound described above, each R^(a) isindependently C₁-C₆alkyl.

In some embodiments of a compound described above, each R^(b) isindependently hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆deuteroalkyl,or cycloalkyl; wherein each alkyl and cycloalkyl is independentlyoptionally substituted with one or more oxo, deuterium, halogen, —CN,—OH, —OMe, —NH₂, —C(═O)Me, —C(═O)OH, —C(═O)OMe, C₁-C₆alkyl, orC₁-C₆haloalkyl. In some embodiments of a compound described above, eachR^(b) is independently hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl, orC₁-C₆deuteroalkyl. In some embodiments of a compound described above,each R^(b) is independently C₁-C₆alkyl or C₁-C₆deuteroalkyl. In someembodiments of a compound described above, each R^(b) is independentlyhydrogen or C₁-C₆alkyl. In some embodiments of a compound describedabove, each R^(b) is hydrogen. In some embodiments of a compounddescribed above, each R^(b) is independently C₁-C₆alkyl.

In some embodiments of a compound described above, each R^(c) and R^(d)is independently hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl,C₁-C₆deuteroalkyl, or cycloalkyl; wherein each alkyl and cycloalkyl isindependently optionally substituted with one or more oxo, deuterium,halogen, —CN, —OH, —OMe, —NH₂, —C(═O)Me, —C(═O)OH, —C(═O)OMe,C₁-C₆alkyl, or C₁-C₆haloalkyl. In some embodiments of a compounddescribed above, each R^(c) and R^(d) is independently hydrogen,C₁-C₆alkyl, C₁-C₆haloalkyl, or C₁-C₆deuteroalkyl. In some embodiments ofa compound described above, each R^(c) and R^(d) is independentlyhydrogen or C₁-C₆alkyl. In some embodiments of a compound describedabove, each R^(c) and R^(d) is hydrogen. In some embodiments of acompound described above, each R^(c) and R^(d) is independentlyC₁-C₆alkyl.

Disclosed herein is a compound, or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, selected from the group consisting of:

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Disclosed herein is a compound, or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, selected from the group consisting of:

Disclosed herein is a compound, or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, selected from the group consisting of:

Disclosed herein is a compound, or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, selected from the group consisting of:

Disclosed herein is a compound, or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, selected from the group consisting of:

Disclosed herein is a compound, or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, selected from the group consisting of:

Disclosed herein is a compound, or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, selected from the group consisting of:

Disclosed herein is a compound, or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, selected from the group consisting of:

Disclosed herein is a compound, or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, selected from the group consisting of:

Disclosed herein is a compound, or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, selected from the group consisting of:

Disclosed herein is a compound, or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, selected from the group consisting of:

Disclosed herein is a compound, or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, selected from the group consisting of:

Disclosed herein is a compound, or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, selected from the group consisting of:

Disclosed herein is a compound, or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, selected from the group consisting of:

Disclosed herein is a compound, or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, selected from the group consisting of:

Disclosed herein is a compound, or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, selected from the group consisting of:

Disclosed herein is a compound, or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof selected from the group consisting of:

wherein:

-   -   R₁=-Et, —CH₂—CD₃, or cyclopropyl;    -   R₂=ME, CD₃, or Et    -   R₃=Isopropyl, cyclobutyl, cyclopropyl, or t-butyl.

Further Forms of Compounds Disclosed Herein

Isomers Stereoisomers

In some embodiments, the compounds described herein exist as geometricisomers. In some embodiments, the compounds described herein possess oneor more double bonds. The compounds presented herein include all cis,trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as thecorresponding mixtures thereof. In some situations, the compoundsdescribed herein possess one or more chiral centers and each centerexists in the R configuration or S configuration. The compoundsdescribed herein include all diastereomeric, enantiomeric, and epimericforms as well as the corresponding mixtures thereof. In additionalembodiments of the compounds and methods provided herein, mixtures ofenantiomers and/or diastereoisomers, resulting from a single preparativestep, combination, or interconversion are useful for the applicationsdescribed herein. In some embodiments, the compounds described hereinare prepared as their individual stereoisomers by reacting a racemicmixture of the compound with an optically active resolving agent to forma pair of diastereoisomeric compounds, separating the diastereomers, andrecovering the optically pure enantiomers. In some embodiments,dissociable complexes are preferred. In some embodiments, thediastereomers have distinct physical properties (e.g., melting points,boiling points, solubilities, reactivity, etc.) and are separated bytaking advantage of these dissimilarities. In some embodiments, thediastereomers are separated by chiral chromatography, or preferably, byseparation/resolution techniques based upon differences in solubility.In some embodiments, the optically pure enantiomer is then recovered,along with the resolving agent.

Labeled Compounds

In some embodiments, the compounds described herein exist in theirisotopically-labeled forms. In some embodiments, the methods disclosedherein include methods of treating diseases by administering suchisotopically-labeled compounds. In some embodiments, the methodsdisclosed herein include methods of treating diseases by administeringsuch isotopically-labeled compounds as pharmaceutical compositions.Thus, in some embodiments, the compounds disclosed herein includeisotopically-labeled compounds, which are identical to those recitedherein, but for the fact that one or more atoms are replaced by an atomhaving an atomic mass or mass number different from the atomic mass ormass number usually found in nature. Examples of isotopes that can beincorporated into compounds described herein, or a solvate, orstereoisomer thereof, include isotopes of hydrogen, carbon, nitrogen,oxygen, phosphorous, sulfur, fluorine, and chloride, such as ²H, ³H,¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl, respectively.Compounds described herein, and the pharmaceutically acceptable salts,solvates, or stereoisomers thereof which contain the aforementionedisotopes and/or other isotopes of other atoms are within the scope ofthis disclosure. Certain isotopically labeled compounds, for examplethose into which radioactive isotopes such as ³H and ¹⁴C areincorporated, are useful in drug and/or substrate tissue distributionassays. Tritiated, i.e., ³H and carbon-14, i.e., ¹⁴C, isotopes areparticularly preferred for their ease of preparation and detectability.Further, substitution with heavy isotopes such as deuterium, i.e., ²H,produces certain therapeutic advantages resulting from greater metabolicstability, for example increased in vivo half-life or reduced dosagerequirements. In some embodiments, the isotopically labeled compound ora pharmaceutically acceptable salt, solvate, or stereoisomer thereof isprepared by any suitable method.

In some embodiments, the compounds described herein are labeled by othermeans, including, but not limited to, the use of chromophores orfluorescent moieties, bioluminescent labels, or chemiluminescent labels.

Pharmaceutically Acceptable Salts

In some embodiments, the compounds described herein exist as theirpharmaceutically acceptable salts. In some embodiments, the methodsdisclosed herein include methods of treating diseases by administeringsuch pharmaceutically acceptable salts. In some embodiments, the methodsdisclosed herein include methods of treating diseases by administeringsuch pharmaceutically acceptable salts as pharmaceutical compositions.

In some embodiments, the compounds described herein possess acidic orbasic groups and therefor react with any of a number of inorganic ororganic bases, and inorganic and organic acids, to form apharmaceutically acceptable salt. In some embodiments, these salts areprepared in situ during the final isolation and purification of thecompounds disclosed herein, or by separately reacting a purifiedcompound in its free form with a suitable acid or base, and isolatingthe salt thus formed.

Examples of pharmaceutically acceptable salts include those saltsprepared by reaction of the compounds described herein with a mineral,organic acid, or inorganic base, such salts including acetate, acrylate,adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate,bisulfite, bromide, butyrate, butyn-1,4-dioate, camphorate,camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride,citrate, cyclopentanepropionate, decanoate, digluconate,dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptanoate, glycerophosphate, glycolate,hemisulfate, heptanoate, hexanoate, hexyne-1,6-dioate, hydroxybenzoate,γ-hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide,2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate,malonate, methanesulfonate, mandelate metaphosphate, methanesulfonate,methoxybenzoate, methylbenzoate, monohydrogenphosphate,1-napthalenesulfonate, 2-napthalenesulfonate, nicotinate, nitrate,palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate,phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate,sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate,thiocyanate, tosylateundeconate, and xylenesulfonate.

Further, the compounds described herein can be prepared aspharmaceutically acceptable salts formed by reacting the free base formof the compound with a pharmaceutically acceptable inorganic or organicacid, including, but not limited to, inorganic acids such ashydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid metaphosphoric acid, and the like; and organic acidssuch as acetic acid, propionic acid, hexanoic acid,cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid,malonic acid, succinic acid, malic acid, maleic acid, fumaric acid,p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citricacid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid,mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonicacid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid,benzenesulfonic acid, 2-naphthalenesulfonic acid,4-methylbicyclo-[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid,4,4′-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionicacid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuricacid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylicacid, stearic acid, and muconic acid.

In some embodiments, those compounds described herein which comprise afree acid group react with a suitable base, such as the hydroxide,carbonate, bicarbonate, or sulfate of a pharmaceutically acceptablemetal cation, with ammonia, or with a pharmaceutically acceptableorganic primary, secondary, tertiary, or quaternary amine.Representative salts include the alkali or alkaline earth salts, likelithium, sodium, potassium, calcium, and magnesium, and aluminum saltsand the like. Illustrative examples of bases include sodium hydroxide,potassium hydroxide, choline hydroxide, sodium carbonate, N⁺(C₁₋₄alkyl)₄, and the like.

Representative organic amines useful for the formation of base additionsalts include ethylamine, diethylamine, ethylenediamine, ethanolamine,diethanolamine, piperazine, and the like. It should be understood thatthe compounds described herein also include the quaternization of anybasic nitrogen-containing groups they contain. In some embodiments,water or oil-soluble or dispersible products are obtained by suchquaternization.

Solvates

In some embodiments, the compounds described herein exist as solvates.The disclosure provides for methods of treating diseases byadministering such solvates. The disclosure further provides for methodsof treating diseases by administering such solvates as pharmaceuticalcompositions.

Solvates contain either stoichiometric or non-stoichiometric amounts ofa solvent, and, in some embodiments, are formed during the process ofcrystallization with pharmaceutically acceptable solvents such as water,ethanol, and the like. Hydrates are formed when the solvent is water, oralcoholates are formed when the solvent is alcohol. Solvates of thecompounds described herein can be conveniently prepared or formed duringthe processes described herein. In addition, the compounds providedherein can exist in unsolvated as well as solvated forms. In general,the solvated forms are considered equivalent to the unsolvated forms forthe purposes of the compounds and methods provided herein.

Tautomers

In some situations, compounds exist as tautomers. The compoundsdescribed herein include all possible tautomers within the formulasdescribed herein. Tautomers are compounds that are interconvertible bymigration of a hydrogen atom, accompanied by a switch of a single bondand adjacent double bond. In bonding arrangements where tautomerizationis possible, a chemical equilibrium of the tautomers will exist. Alltautomeric forms of the compounds disclosed herein are contemplated. Theexact ratio of the tautomers depends on several factors, includingtemperature, solvent, and pH.

Preparation of the Compounds

The compounds used in the reactions described herein are made accordingto organic synthesis techniques known to those skilled in this art,starting from commercially available chemicals and/or from compoundsdescribed in the chemical literature. “Commercially available chemicals”are obtained from standard commercial sources including Acros Organics(Pittsburgh, Pa.), Aldrich Chemical (Milwaukee, Wis., including SigmaChemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), AvocadoResearch (Lancashire, U.K.), BDH, Inc. (Toronto, Canada), Bionet(Cornwall, U.K.), Chem Service Inc. (West Chester, Pa.), CrescentChemical Co. (Hauppauge, N.Y.), Eastman Organic Chemicals, Eastman KodakCompany (Rochester, N.Y)., Fisher Scientific Co. (Pittsburgh, Pa.),Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan,Utah), ICN Biomedicals, Inc. (Costa Mesa, Calif.), Key Organics(Cornwall, U.K.), Lancaster Synthesis (Windham, N.H.), MaybridgeChemical Co. Ltd. (Cornwall, U.K.), Parish Chemical Co. (Orem, Utah),Pfaltz & Bauer, Inc. (Waterbury, CN), Polyorganix (Houston, Tex.),Pierce Chemical Co. (Rockford, Ill.), Riedel de Haen AG (Hanover,Germany), Spectrum Quality Product, Inc. (New Brunswick, N.J.), TCIAmerica (Portland, Oreg.), Trans World Chemicals, Inc. (Rockville, Md.),and Wako Chemicals USA, Inc. (Richmond, Va.).

Suitable reference books and treatises that detail the synthesis ofreactants useful in the preparation of compounds described herein, orprovide references to articles that describe the preparation, includefor example, “Synthetic Organic Chemistry”, John Wiley & Sons, Inc., NewYork; S. R. Sandler et al., “Organic Functional Group Preparations,” 2ndEd., Academic Press, New York, 1983; H. O. House, “Modern SyntheticReactions”, 2nd Ed., W. A. Benjamin, Inc. Menlo Park, Calif. 1972; T. L.Gilchrist, “Heterocyclic Chemistry”, 2nd Ed., John Wiley & Sons, NewYork, 1992; J. March, “Advanced Organic Chemistry: Reactions, Mechanismsand Structure”, 4th Ed., Wiley-Interscience, New York, 1992. Additionalsuitable reference books and treatises that detail the synthesis ofreactants useful in the preparation of compounds described herein, orprovide references to articles that describe the preparation, includefor example, Fuhrhop, J. and Penzlin G. “Organic Synthesis: Concepts,Methods, Starting Materials”, Second, Revised and Enlarged Edition(1994) John Wiley & Sons ISBN: 3-527-29074-5; Hoffman, R. V. “OrganicChemistry, An Intermediate Text” (1996) Oxford University Press, ISBN0-19-509618-5; Larock, R. C. “Comprehensive Organic Transformations: AGuide to Functional Group Preparations” 2nd Edition (1999) Wiley-VCH,ISBN: 0-471-19031-4; March, J. “Advanced Organic Chemistry: Reactions,Mechanisms, and Structure” 4th Edition (1992) John Wiley & Sons, ISBN:0-471-60180-2; Otera, J. (editor) “Modern Carbonyl Chemistry” (2000)Wiley-VCH, ISBN: 3-527-29871-1; Patai, S. “Patai's 1992 Guide to theChemistry of Functional Groups” (1992) Interscience ISBN: 0-471-93022-9;Solomons, T. W. G. “Organic Chemistry” 7th Edition (2000) John Wiley &Sons, ISBN: 0-471-19095-0; Stowell, J. C., “Intermediate OrganicChemistry” 2nd Edition (1993) Wiley-Interscience, ISBN: 0-471-57456-2;“Industrial Organic Chemicals: Starting Materials and Intermediates: AnUllmann's Encyclopedia” (1999) John Wiley & Sons, ISBN: 3-527-29645-X,in 8 volumes; “Organic Reactions” (1942-2000) John Wiley & Sons, in over55 volumes; and “Chemistry of Functional Groups” John Wiley & Sons, in73 volumes.

Specific and analogous reactants are optionally identified through theindices of known chemicals prepared by the Chemical Abstract Service ofthe American Chemical Society, which are available in most public anduniversity libraries, as well as through on-line. Chemicals that areknown but not commercially available in catalogs are optionally preparedby custom chemical synthesis houses, where many of the standard chemicalsupply houses (e.g., those listed above) provide custom synthesisservices. A reference for the preparation and selection ofpharmaceutical salts of the compounds described herein is P. H. Stahl &C. G. Wermuth “Handbook of Pharmaceutical Salts”, Verlag HelveticaChimica Acta, Zurich, 2002.

Pharmaceutical Compositions

In certain embodiments, the compound described herein is administered asa pure chemical. In some embodiments, the compound described herein iscombined with a pharmaceutically suitable or acceptable carrier (alsoreferred to herein as a pharmaceutically suitable (or acceptable)excipient, physiologically suitable (or acceptable) excipient, orphysiologically suitable (or acceptable) carrier) selected on the basisof a chosen route of administration and standard pharmaceutical practiceas described, for example, in Remington: The Science and Practice ofPharmacy (Gennaro, 21^(st) Ed. Mack Pub. Co., Easton, Pa. (2005)).

Accordingly, provided herein is a pharmaceutical composition comprisinga compound described herein, or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, and a pharmaceutically acceptableexcipient.

In certain embodiments, the compound provided herein is substantiallypure, in that it contains less than about 5%, or less than about 1%, orless than about 0.1%, of other organic small molecules, such asunreacted intermediates or synthesis by-products that are created, forexample, in one or more of the steps of a synthesis method.

Pharmaceutical compositions are administered in a manner appropriate tothe disease to be treated (or prevented). An appropriate dose and asuitable duration and frequency of administration will be determined bysuch factors as the condition of the patient, the type and severity ofthe patient's disease, the particular form of the active ingredient, andthe method of administration. In general, an appropriate dose andtreatment regimen provides the composition(s) in an amount sufficient toprovide therapeutic and/or prophylactic benefit (e.g., an improvedclinical outcome, such as more frequent complete or partial remissions,or longer disease-free and/or overall survival, or a lessening ofsymptom severity. Optimal doses are generally determined usingexperimental models and/or clinical trials. The optimal dose dependsupon the body mass, weight, or blood volume of the patient.

In some embodiments, the pharmaceutical composition is formulated fororal, topical (including buccal and sublingual), rectal, vaginal,transdermal, parenteral, intrapulmonary, intradermal, intrathecal andepidural and intranasal administration. Parenteral administrationincludes intramuscular, intravenous, intraarterial, intraperitoneal, orsubcutaneous administration. In some embodiments, the pharmaceuticalcomposition is formulated for intravenous injection, oraladministration, inhalation, nasal administration, topicaladministration, or ophthalmic administration. In some embodiments, thepharmaceutical composition is formulated for oral administration. Insome embodiments, the pharmaceutical composition is formulated forintravenous injection. In some embodiments, the pharmaceuticalcomposition is formulated as a tablet, a pill, a capsule, a liquid, aninhalant, a nasal spray solution, a suppository, a suspension, a gel, acolloid, a dispersion, a suspension, a solution, an emulsion, anointment, a lotion, an eye drop, or an ear drop. In some embodiments,the pharmaceutical composition is formulated as a tablet.

Suitable doses and dosage regimens are determined by conventionalrange-finding techniques known to those of ordinary skill in the art.Generally, treatment is initiated with smaller dosages that are lessthan the optimum dose of the compound disclosed herein. Thereafter, thedosage is increased by small increments until the optimum effect underthe circumstances is reached. In some embodiments, the present methodinvolve the administration of about 0.1 μg to about 50 mg of at leastone compound described herein per kg body weight of the subject. For a70 kg patient, dosages of from about 10 μg to about 200 mg of thecompound disclosed herein would be more commonly used, depending on asubject's physiological response.

By way of example only, the dose of the compound described herein formethods of treating a disease as described herein is about 0.001 toabout 1 mg/kg body weight of the subject per day, for example, about0.001 mg, about 0.002 mg, about 0.005 mg, about 0.010 mg, 0.015 mg,about 0.020 mg, about 0.025 mg, about 0.050 mg, about 0.075 mg, about0.1 mg, about 0.15 mg, about 0.2 mg, about 0.25 mg, about 0.5 mg, about0.75 mg, or about 1 mg/kg body weight per day. In some embodiments, thedose of compound described herein for the described methods is about 1to about 1000 mg/kg body weight of the subject being treated per day,for example, about 1 mg, about 2 mg, about 5 mg, about 10 mg, about 15mg, about 20 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg,about 150 mg, about 200 mg, about 250 mg, about 500 mg, about 750 mg, orabout 1000 mg per day.

Methods of Treatment

The compounds disclosed herein, or pharmaceutically acceptable salts,solvates, or stereoisomers thereof, are useful for the inhibition ofkinase activity of one or more enzymes. In some embodiments the kinaseinhibited by the compounds and methods is TYK2.

Provided herein are compounds that are inhibitors of TYK2 and aretherefore useful for treating one or more disorders associated withactivity of TYK2 or mutants thereof.

Provided herein are methods for treating a disease or disorder, whereinthe disease or disorder is an autoimmune disorders, inflammatorydisorders, proliferative disorders, endocrine disorders, neurologicaldisorders, or disorders associated with transplantation, said methodcomprising administering to a patient in need thereof, a pharmaceuticalcomposition comprising an effective amount of a compound describedherein, or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof.

In some embodiments, the disease or disorder is an autoimmune disorder.In some embodiments the disease or disorder is selected from type 1diabetes, systemic lupus erythematosus, multiple sclerosis, psoriasis,Behcet's disease, POEMS syndrome, Crohn's disease, ulcerative colitis,and inflammatory bowel disease.

In some embodiments, the disease or disorder is an inflammatorydisorder. In some embodiments, the inflammatory disorder is rheumatoidarthritis, asthma, chronic obstructive pulmonary disease, psoriasis,hepatomegaly, Crohn's disease, ulcerative colitis, inflammatory boweldisease.

In some embodiments, the disease or disorder is a proliferativedisorder. In some embodiments, the proliferative disorder is ahematological cancer. In some embodiments the proliferative disorder isa leukemia. In some embodiments, the leukemia is a T-cell leukemia. Insome embodiments the T-cell leukemia is T-cell acute lymphoblasticleukemia (T-ALL). In some embodiments the proliferative disorder ispolycythemia vera, myelofibrosis, essential or thrombocytosis.

In some embodiments, the disease or disorder is an endocrine disorder.In some embodiments, the endocrine disorder is polycystic ovarysyndrome, Crouzon's syndrome, or type 1 diabetes.

In some embodiments, the disease or disorder is a neurological disorder.In some embodiments, the neurological disorder is Alzheimer's disease.

In some embodiments the proliferative disorder is associated with one ormore activating mutations in TYK2. In some embodiments, the activatingmutation in TYK2 is a mutation to the FERM domain, the JH2 domain, orthe kinase domain. In some embodiments the activating mutation in TYK2is selected from G36D, S47N, R425H, V731I, E957D, and R1027H.

In some embodiments, the disease or disorder is associated withtransplantation. In some embodiments the disease or disorder associatedwith transplantation is transplant rejection, or graft versus hostdisease.

In some embodiments the disease or disorder is associated with type Iinterferon, IL-10, IL-12, or IL-23 signaling. In some embodiments thedisease or disorder is associated with type I interferon signaling. Insome embodiments the disease or disorder is associated with IL-10signaling. In some embodiments the disorder is associated with IL-12signaling. In some embodiments the disease or disorder is associatedwith IL-23 signaling.

Provided herein are methods for treating an inflammatory or allergiccondition of the skin, for example psoriasis, contact dermatitis, atopicdermatitis, alopecia areata, erythema multiforma, dermatitisherpetiformis, scleroderma, vitiligo, hypersensitivity angiitis,urticaria, bullous pemphigoid, lupus erythematosus, systemic lupuserythematosus, pemphigus vulgaris, pemphigus foliaceus, paraneoplasticpemphigus, epidermolysis bullosa acquisita, acne vulgaris, and otherinflammatory or allergic conditions of the skin.

Provided herein are methods for treating other diseases or conditions,such as diseases or conditions having an inflammatory component, forexample, treatment of diseases and conditions of the eye such as ocularallergy, conjunctivitis, keratoconjunctivitis sicca, and vernalconjunctivitis, diseases affecting the nose including allergic rhinitis,and inflammatory disease in which autoimmune reactions are implicated orhaving an autoimmune component or etiology, including autoimmunehematological disorders (e.g. hemolytic anemia, aplastic anemia, purered cell anemia and idiopathic thrombocytopenia), systemic lupuserythematosus, rheumatoid arthritis, polychondritis, scleroderma,Wegener granulamatosis, dermatomyositis, chronic active hepatitis,myasthenia gravis, Steven-Johnson syndrome, idiopathic sprue, autoimmuneinflammatory bowel disease (e.g. ulcerative colitis and Crohn'sdisease), irritable bowel syndrome, celiac disease, periodontitis,hyaline membrane disease, kidney disease, glomerular disease, alcoholicliver disease, multiple sclerosis, endocrine opthalmopathy, Grave'sdisease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis,multiple sclerosis, primary biliary cirrhosis, uveitis (anterior andposterior), Sjogren's syndrome, keratoconjunctivitis sicca and vernalkeratoconjunctivitis, interstitial lung fibrosis, psoriatic arthritis,systemic juvenile idiopathic arthritis, cryopyrin-associated periodicsyndrome, nephritis, vasculitis, diverticulitis, interstitial cystitis,glomerulonephritis (with and without nephrotic syndrome, e.g. includingidiopathic nephrotic syndrome or minal change nephropathy), chronicgranulomatous disease, endometriosis, leptospiriosis renal disease,glaucoma, retinal disease, ageing, headache, pain, complex regional painsyndrome, cardiac hypertrophy, musclewasting, catabolic disorders,obesity, fetal growth retardation, hyperchlolesterolemia, heart disease,chronic heart failure, mesothelioma, anhidrotic ecodermal dysplasia,Behcet's disease, incontinentia pigmenti, Paget's disease, pancreatitis,hereditary periodic fever syndrome, asthma (allergic and non-allergic,mild, moderate, severe, bronchitic, and exercise-induced), acute lunginjury, acute respiratory distress syndrome, eosinophilia,hypersensitivities, anaphylaxis, nasal sinusitis, ocular allergy, silicainduced diseases, COPD (reduction of damage, airways inflammation,bronchial hyperreactivity, remodeling or disease progression), pulmonarydisease, cystic fibrosis, acid-induced lung injury, pulmonaryhypertension, polyneuropathy, cataracts, muscle inflammation inconjunction with systemic sclerosis, inclusion body myositis, myastheniagravis, thyroiditis, Addison's disease, lichen planus, Type 1 diabetes,or Type 2 diabetes, appendicitis, atopic dermatitis, asthma, allergy,blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis,cholangitis, cholecystitis, chronic graft rejection, colitis,conjunctivitis, Crohn's disease, cystitis, dacryoadenitis, dermatitis,dermatomyositis, encephalitis, endocarditis, endometritis, enteritis,enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis,gastritis, gastroenteritis, Henoch-Schonlein purpura, hepatitis,hidradenitis suppurativa, immunoglobulin A nephropathy, interstitiallung disease, laryngitis, mastitis, meningitis, myelitis myocarditis,myositis, nephritis, oophoritis, orchitis, osteitis, otitis,pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis,pleuritis, phlebitis, pneumonitis, pneumonia, polymyositis, proctitis,prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis,stomatitis, synovitis, tendonitis, tonsillitis, ulcerative colitis,uveitis, vaginitis, vasculitis, or vulvitis.

In some embodiments the inflammatory disease is acute and chronic gout,chronic gouty arthritis, psoriasis, psoriatic arthritis, rheumatoidarthritis, Juvenile rheumatoid arthritis, Systemic juvenile idiopathicarthritis (SJIA), Cryopyrin Associated Periodic Syndrome (CAPS), orosteoarthritis.

In some embodiments the inflammatory disease is a Th1 or Th17 mediateddisease. In some embodiments the Th17 mediated disease is selected fromSystemic lupus erythematosus, Multiple sclerosis, and inflammatory boweldisease (including Crohn's disease or ulcerative colitis).

In some embodiments the inflammatory disease is Sjogren's syndrome,allergic disorders, osteoarthritis, conditions of the eye such as ocularallergy, conjunctivitis, keratoconjunctivitis sicca, vernalconjunctivitis, or diseases affecting the nose such as allergicrhinitis.

Combination Therapy

In certain instances, the compound described herein, or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, isadministered in combination with a second therapeutic agent.

In some embodiments, the benefit experienced by a patient is increasedby administering one of the compounds described herein with a secondtherapeutic agent (which also includes a therapeutic regimen) that alsohas therapeutic benefit.

In one specific embodiment, a compound described herein, or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, isco-administered with a second therapeutic agent, wherein the compounddescribed herein, or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, and the second therapeutic agent modulatedifferent aspects of the disease, disorder or condition being treated,thereby providing a greater overall benefit than administration ofeither therapeutic agent alone.

In any case, regardless of the disease, disorder or condition beingtreated, the overall benefit experienced by the patient is simplyadditive of the two therapeutic agents or the patient experiences asynergistic benefit.

In certain embodiments, different therapeutically-effective dosages ofthe compounds disclosed herein will be utilized in formulating apharmaceutical composition and/or in treatment regimens when thecompounds disclosed herein are administered in combination with a secondtherapeutic agent. Therapeutically-effective dosages of drugs and otheragents for use in combination treatment regimens are optionallydetermined by means similar to those set forth hereinabove for theactives themselves. Furthermore, the methods of prevention/treatmentdescribed herein encompasses the use of metronomic dosing, i.e.,providing more frequent, lower doses in order to minimize toxic sideeffects. In some embodiments, a combination treatment regimenencompasses treatment regimens in which administration of a compounddescribed herein, or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof is initiated prior to, during, or after treatmentwith a second agent described herein, and continues until any timeduring treatment with the second agent or after termination of treatmentwith the second agent. It also includes treatments in which a compounddescribed herein, or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, and the second agent being used in combination areadministered simultaneously or at different times and/or at decreasingor increasing intervals during the treatment period. Combinationtreatment further includes periodic treatments that start and stop atvarious times to assist with the clinical management of the patient.

It is understood that the dosage regimen to treat, prevent, orameliorate the condition(s) for which relief is sought, is modified inaccordance with a variety of factors (e.g. the disease, disorder orcondition from which the subject suffers; the age, weight, sex, diet,and medical condition of the subject). Thus, in some instances, thedosage regimen actually employed varies and, in some embodiments,deviates from the dosage regimens set forth herein.

For combination therapies described herein, dosages of theco-administered compounds vary depending on the type of co-drugemployed, on the specific drug employed, on the disease or conditionbeing treated, and so forth. In additional embodiments, whenco-administered with a second therapeutic agent, the compound providedherein is administered either simultaneously with the second therapeuticagent, or sequentially.

In combination therapies, the multiple therapeutic agents (one of whichis one of the compounds described herein) are administered in any orderor even simultaneously. If administration is simultaneous, the multipletherapeutic agents are, by way of example only, provided in a single,unified form, or in multiple forms (e.g., as a single pill or as twoseparate pills).

The compounds described herein, or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, as well as combination therapies, areadministered before, during, or after the occurrence of a disease orcondition, and the timing of administering the composition containing acompound varies. Thus, in one embodiment, the compounds described hereinare used as a prophylactic and are administered continuously to subjectswith a propensity to develop conditions or diseases in order to preventthe occurrence of the disease or condition. In another embodiment, thecompounds and compositions are administered to a subject during or assoon as possible after the onset of the symptoms. In specificembodiments, a compound described herein is administered as soon as ispracticable after the onset of a disease or condition is detected orsuspected, and for a length of time necessary for the treatment of thedisease. In some embodiments, the length required for treatment varies,and the treatment length is adjusted to suit the specific needs of eachsubject. For example, in specific embodiments, a compound describedherein or a formulation containing the compound is administered for atleast 2 weeks, about 1 month to about 5 years.

In some embodiments, the compound of described herein, or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, isadministered in combination with an adjuvant. In one embodiment, thetherapeutic effectiveness of one of the compounds described herein isenhanced by administration of an adjuvant (i.e., by itself the adjuvanthas minimal therapeutic benefit, but in combination with anothertherapeutic agent, the overall therapeutic benefit to the patient isenhanced).

EXAMPLES Intermediate A

Step 1: Synthesis of Compound Ab

To a solution of methyl 2-hydroxy-3-nitrobenzoate (10 g, 50.7 mmol) inDMF (100 mL) at room temperature was added potassium carbonate (14.02 g,101 mmol) followed by addition of methyl iodide (6.34 mL, 101 mmol) andthe resulting orange mixture was heated to 60° C. for 1 h. The reactionwas cooled to room temperature and then crushed ice (˜100 mL) was added,followed by water to a total volume of ˜400 mL 10 causing a yellow solidto crystallize from solution. The slurry was stirred for a few minutesand then collected by vacuum filtration and the resulting initiallyyellow solid was rinsed with additional water (˜100 mL) until all of theyellow color was rinsed into the filtrate giving a near white solid inthe funnel. Partially air-dried solid in funnel then transferred to aflask and further dried under vacuum over night to afford Ab (10.5 g,98%) of a yellow solid as the desired product. LCMS [M+1]⁺=197.1.

Step 2: Synthesis of Compound Ac

Methyl 2-methoxy-3-nitrobenzoate (11 g, 52.1 mmol) was dissolved in acold solution of ammonia in methanol (7 N, 250 mL) and conc. aqueousammonium hydroxide (100 mL) was added. The flask was sealed and theresulting solution was allowed to gently stir at room temperatureovernight (˜17 h). The reaction mixture was concentrated to afford Ac(1.67 g, 86%) as a yellow solid. LCMS [M+1]⁺=196.1.

Step 3: Synthesis of Compound Ad

2-methoxy-3-nitrobenzamide (6.5 g, 33.1 mmol) was slurried in dimethylformamide dimethyl acetal (39.5 g, 331 mmol) and the mixture was heatedto 95° C. giving a clear, pale yellow solution. After heating for ˜30min at 95° C., the reaction was cooled and was concentrated on therotovap and the resulting yellow oil was azeotroped twice with1,2-dichloroethane (40 mL portions) to ensure complete removal of anyresidual dimethyl formamide dimethyl acetal. The crude oil thus obtainedwas immediately dissolved in 35 mL of ethanol and was immediately usedin the following step.

In a separate flask was prepared a mixture of ethanol (150 mL) andacetic acid (AcOH, 35 mL) and the resulting solution was cooled in anice bath. Once cooled, hydrazine hydrate (16.1 mL, 331 mmol) was addeddropwise. At this time, the solution containing the crude dimethylformamide dimethyl acetal adduct as prepared above was transferreddropwise over ˜15 min by cannula into the previously preparedwell-stirred ice-cold mixture containing the hydrazine. During theaddition, a pale yellow solid formed in the solution. After the additionwas complete, the resulting cloudy yellow mixture was allowed to warm toroom temperature and stir for 4 h. The reaction mixture at this time wasconcentrated on the rotovap to remove some of the ethanol, diluted withadditional water and filtered to collect the solid. The solid was washedwith additional portions of water, air dried in the funnel then undervacuum to afford Ad (4.0 g, 54.8%) of a pale yellow solid as the desiredproduct. LCMS [M+1]⁺=221.1.

Step 4: Synthesis of Compound Ae

A solution of 3-(2-methoxy-3-nitrophenyl)-4H-1,2,4-triazole (5.00 g,22.71 mmol) in DMF (20 mL) was treated with potassium carbonate (4.20 g,30.4 mmol). After cooling the resulting mixture in an ice bath, asolution of iodomethane (4.20 g, 29.59 mmol) in DMF (5 mL) was slowlyadded dropwise by syringe over 2 min. After the addition was complete,the ice bath was removed and the reaction mixture was allowed to warm tort. After stirring at room temperature for ˜4 h, LCMS analysis indicatedcomplete and clean conversion to the region-isomeric mixture of productsin ˜2:1 ratio, respectively. The reaction was cooled in an ice bath andwas diluted with water (˜50 mL) and the solution was extracted withEtOAc (3×40 mL) and the combined extracts were washed with 10% aq. LiCl(2×20 mL), water (20 mL) then brine (20 mL), concentrated and purifiedby CC to afford Ae (2.0 g, 38%) of the major isomer as a pale yellowsolid. LCMS [M+1]⁺=235.1. ¹H NMR (400 MHz, methanol-d₆) δ 8.50 (s, 1H),8.11 (dd, J=7.9, 1.8 Hz, 1H), 7.85 (dd, J=8.1, 1.8 Hz, 1H), 7.38 (t,J=8.0 Hz, 1H), 4.03 (s, 3H), 3.83 (s, 3H).

Step 5: Synthesis of Intermediate A

A solution of 3-(2-methoxy-3-nitrophenyl)-1-methyl-1H-1,2,4-triazole(2.20 g, 10.77 mmol) in EtOH (50 mL) was sparged with nitrogen for a fewminutes before adding 10% Pd-C (0.90 g, 0.43 mmol) followed by spargingwith hydrogen from a balloon for a few minutes then allowing the mixtureto stir under a balloon of hydrogen for 1.5 h at rt. The mixture wasthen sparged with nitrogen to deactivate the catalyst and the mixturewas filtered through a pad of celite washing with additional amounts ofEtOH and the resulting clear, colorless filtrate containing the productwas concentrated and purified by CC to afford an off-white solidIntermediate A (1.5 g, 68%). LCMS [M+1]⁺=205.2. ¹H NMR (400 MHz,chloroform-d) δ 8.09 (s, 1H), 7.35 (dd, J=7.8, 1.7 Hz, 1H), 7.00 (t,J=7.8 Hz, 1H), 6.82 (dd, J=7.8, 1.7 Hz, 1H), 4.00 (s, 3H), 3.94 (s, 2H),3.78 (s, 3H).

Intermediate 1

Step 1: Synthesis of Compound Xb

Xa (10 g, 64.1 mmol) was placed in a 1 L flask and triethylamine (8.9mL, 64.1 mmol) was added, followed by phosphorus oxychloride (50 mL, 546mmol). the mixture was heated to 110° C. and stirred for 120 minutes,then concentrated under reduced pressure. 200 mL of anhydrous1,2-dichloroethane was added to the residue and the mixture sonicatedand then concentrated. the residue was dissolved in THF (200 mL),deuteromethylamine (HCl salt, 2.26 g, 32 mmol) was then added, followedby N,N′-diisopropylethylamine (18 mL, 103 mmol). After 1 hour thereaction was concentrated and the residue adsorbed onto celite usingdichloromethane. The filtrate was re-concentrated and purified by CC toafford a yellow solid Xb (5.1 g, 37%).

Step 2: Synthesis of Intermediate 1

To a solution of Xb (5.00 g, 23.92 mmol) and intermediate A (4.88 g,23.92 mmol) in THF (50 mL) under N₂ was added LiHMDS (1 M, 71.80 mL,71.80 mmol) at 0° C. resulting a mild exotherm. The reaction was stirredat r.t. for 3 h. The reaction mixture was cooled to 0° C., quenched byadding satd. NH₄Cl (aq.), diluted with water (100 mL) and extracted byEtOAc (50 mL×3). The combined organic layers were washed by brine (50mL), dried over Na₂SO₄, filtered and concentrated under reduced pressureto afford the crude product which was purified by column chromatography(DCM/EtOAc=3/1) to give the desired product Intermediate 1 (6.5 g,yield: 72.2%) as a yellow solid. LCMS=[M+1]⁺=377.1.

Intermediate 2

Step 1: Synthesis of Compound 2Ae

A solution of 3-(2-methoxy-3-nitrophenyl)-4H-1,2,4-triazole (Ad) (5.00g, 22.71 mmol) in DMF (20 mL) was treated with potassium carbonate (4.20g, 30.4 mmol). After cooling the resulting mixture in an ice bath, asolution of iodomethane-d₃ (4.20 g, 29.59 mmol) in DMF (5 mL) was slowlyadded dropwise by syringe over 2 min. After the addition was complete,the ice bath was removed and the reaction mixture was allowed to warm tort. After stirring at room temperature for ˜4 h, LCMS analysis indicatedcomplete and clean conversion to the regioisomeric mixture of productsin ˜2:1 ratio, respectively. The reaction was cooled in an ice bath andwas diluted with water (˜50 mL) and the solution was extracted withEtOAc (3×40 mL) and the combined extracts were washed with 10% aq. LiCl(2×20 mL), water (20 mL) then brine (20 mL), concentrated and purifiedby CC to afford 2Ae (2.0 g, 38%) of the major isomer as a pale yellowsolid. LCMS [M+1]⁺=238.1.

Step 2: Synthesis of Compound 2A

A solution of3-(2-methoxy-3-nitrophenyl)-1-(methyl-d3)-1H-1,2,4-triazole (2.20 g,10.77 mmol) in EtOH (50 mL) was sparged with nitrogen for a few minutesbefore adding 10% Pd-C (0.90 g, 0.43 mmol) followed by sparging withhydrogen from a balloon for a few minutes then allowing the mixture tostir under a balloon of hydrogen for 1.5 h at rt. The mixture was thensparged with nitrogen to deactivate the catalyst and the mixture wasfiltered through a pad of CELITE® washing with additional amounts ofEtOH and the resulting clear, colorless filtrate containing the productwas concentrated and purified by CC to afford an off-white solid 2A (1.5g, 68%). LCMS [M+1]⁺=208.2.

Step 3: Synthesis of Intermediate 2

To a solution of Xb (5.00 g, 23.92 mmol) and Example 2A (4.88 g, 23.92mmol) in THF (50 mL) under N₂ was added LiHMDS (1 M, 71.80 mL, 71.80mmol) at 0° C. resulting a mild exotherm. The reaction was stirred atr.t. When completed, The reaction mixture was cooled to 0° C., quenchedby adding satd. NH₄Cl (aq.), diluted with water (100 mL) and extractedby EtOAc (50 mL*3). The combined organic layers were washed by brine (50mL), dried over Na₂SO₄, filtered and concentrated under reduced pressureto afford the crude product which was purified by column chromatography(DCM/EtOAc=3/1) to give the desired product intermediate 2 (6.5 g,yield: 72.2%) as a yellow solid. LCMS [M+1]⁺=380.1.

Intermediate 3A

Step 1: Synthesis of Compound 3Ab

To a solution of methyl 2-hydroxy-3-nitrobenzoate (7 g, 35.5 mmol) inDMF (70 mL) at room temperature was added potassium carbonate (9.8 g,71.0 mmol) followed by addition of iodomethane-d₃ (4.42 mL, 71.0 mmol)and the resulting orange mixture was heated to 60° C. for 1 h. Thereaction was cooled to room temperature and then crushed ice (˜100 mL)was added, followed by water to a total volume of ˜400 mL causing ayellow solid to crystallize from solution. The slurry was stirred for afew minutes and then collected by vacuum filtration and the resultinginitially yellow solid was rinsed with additional water (˜100 mL) untilall of the yellow color was rinsed into the filtrate giving a near whitesolid in the funnel. Partially air-dried solid in funnel thentransferred to a flask and further dried under vacuum overnight toafford 3Ab (6.5 g, 86%) of a yellow solid as the desired product. LCMS[M+1]⁺=215.1.

Step 2: Synthesis of Compound 3Ac

methyl 2-(methoxy-d₃)-3-nitrobenzoate 3Ab (6.5 g, 30.3 mmol) wasdissolved in a cold solution of ammonia in methanol (7N, 140 mL) andconc. aqueous ammonium hydroxide (60 mL) was added. The flask was sealedand the resulting solution was allowed to gently stir at roomtemperature overnight (˜17 h). The reaction mixture was concentrated toafford 3Ac (5.8 g, 96%) as a yellow solid. LCMS [M+1]⁺=200.1

Step 3: Synthesis of Compound 3Ad

2-(methoxy-d₃)-3-nitrobenzamide 3Ac (5.8 g, 29.1 mmol) was slurried indimethyl formamide dimethyl acetal (38.6 mL, 291 mmol) and the mixturewas heated to 95° C. giving a clear, pale yellow solution. After heatingfor ˜30 min at this temp the reaction was cooled and was concentrated onthe rotovap and the resulting yellow oil was azeotroped twice with1,2-dichloroethane (40 mL portions) to ensure complete removal of anyresidual dimethyl formamide dimethyl acetal. The crude oil thus obtainedwas immediately dissolved in 35 mL of ethanol and was immediately usedin the following step.

In a separate flask was prepared a mixture of ethanol (150 mL) andacetic acid (AcOH, 35 mL) and the resulting solution was cooled in anice bath. Once cooled, hydrazine hydrate (14.1 mL, 291 mmol) was addeddropwise. At this time, the solution containing the crude dimethylformamide dimethyl acetal adduct as prepared above was transferreddropwise over ˜15 min by cannula into the previously preparedwell-stirred ice-cold mixture containing the hydrazine. During theaddition, a pale yellow solid formed in the solution. After the additionwas complete, the resulting cloudy yellow mixture was allowed to warm toroom temperature and stir for ˜4 h. The reaction mixture at this timewas concentrated on the rotovap to remove some of the ethanol, dilutedwith additional water and filtered to collect the solid. The solid waswashed with additional portions of water, air dried in the funnel thenunder vacuum to afford 3Ad (5.0 g, 77.0%) of a pale yellow solid as thedesired product. LCMS [M+1]⁺=224.1

Step 4: Synthesis of Compound 3Ae

A solution of 3-(2-(methoxy-d₃)-3-nitrophenyl)-1H-1,2,4-triazole 3Ad(5.00 g, 22.4 mmol) in DMF (20 mL) was treated with potassium carbonate(9.28 g, 67.2 mmol). After cooling the resulting mixture in an ice bath,a solution of iodomethane (1.9 mL, 30.2 mmol) DMF (5 mL) was slowlyadded dropwise by syringe over 2 min. After the addition was complete,the ice bath was removed and the reaction mixture was allowed to warm tort. After stirring at room temperature for ˜4 h, LCMS analysis indicatedcomplete and clean conversion to the regioisomeric mixture of productsin ˜2:1 ratio, respectively. The reaction was cooled in an ice bath andwas diluted with water (˜50 mL) and the solution was extracted withEtOAc (3×40 mL) and the combined extracts were washed with 10% aq. LiCl(2×20 mL), water (20 mL) then brine (20 mL), concentrated and purifiedby CC to afford 3Ae (2.1 g, 39.54%) of the major isomer as a pale yellowsolid. LCMS [M+1]⁺=238.2.

Step 5: Synthesis of Compound 3A

A solution of3-(2-(methoxy-d₃)-3-nitrophenyl)-1-methyl-1H-1,2,4-triazole 3Ae (1.6 g,6.75 mmol) in EtOH (50 mL) was sparged with nitrogen for a few minutesbefore adding 10% Pd-C (0.8 g) followed by sparging with hydrogen from aballoon for a few minutes then allowing the mixture to stir under aballoon of hydrogen for 1.5 h at rt. The mixture was then sparged withnitrogen to deactivate the catalyst and the mixture was filtered througha pad of CELITE® washing with additional amounts of EtOH and theresulting clear, colorless filtrate containing the product wasconcentrated and purified by CC to afford an off-white solid 3A (1.1 g,68%).

LCMS [M+1]⁺=208.2. ¹H NMR (400 MHz, CDCl₃) δ 8.09 (s, 1H) 7.35 (dd, 1H),6.99 (t, 1H), 6.83 (dd, 1H), 3.99 (s, 3H), 3.80-3.45 (m, 2H).

Intermediate 3

To a solution of Xb (0.9 g, 4.32 mmol) and 3A (0.9 g, 4.32 mmol) in THF(15 mL) under N₂ was added LiHMDS (1 M, 13 mL, 13 mmol) at 0° C.resulting a mild exotherm. The reaction was stirred at r.t. Whencompleted, The reaction mixture was cooled to 0° C., quenched by addingsatd. NH₄Cl (aq.), diluted with water (100 mL) and extracted by EtOAc(50 mL×3). The combined organic layers were washed by brine (50 mL),dried over Na₂SO₄, filtered and concentrated under reduced pressure toafford the crude product which was purified by column chromatography(DCM/EtOAc=3/1) to give the desired product intermediate 3 (1.3 g,yield: 79.26%) as a yellow solid. LCMS [M+1]⁺=380.2.

Example 1:4-[2-methoxy-3-(1-methyl-1,2,4-triazol-3-yl)anilino]-6-(2-oxoimidazolidin-1-yl)-N-(trideuteriomethyl)pyridazine-3-carboxamide

Step 1:6-(3-acetyl-2-oxo-imidazolidin-1-yl)-4-[2-methoxy-3-(1-methyl-1,2,4-triazol-3-yl)anilino]-N-(trideuteriomethyl)pyridazine-3-carboxamide

To a solution of intermediate 1 (60 mg, 0.16 mmol) and 1A (41 mg, 0.32mmol) in 1,4-dioxane (8 mL) was added Cesium carbonate (100 mg, 0.32mmol), Pd₂(dba)₃ (43 mg, 0.048 mmol), and xantphos (46 mg, 0.08 mmol).The mixture degassed by N₂ for 3 times and heated to 120 ° C. for 4 hrs.When reaction completed, filtered, filtrate was removed in vacuo,chromatography (PE/EtOAc=50/50 then DCM/MeOH=97/3) to give the desiredproduct Example 1 (6 mg, yield: 8%) as a yellow solid. LM-MS: m/z=469.2[M+H]⁺

Step 2:4-[2-methoxy-3-(1-methyl-1,2,4-triazol-3-yl)anilino]-6-(2-oxoimidazolidin-1-yl)-N-(trideuteriomethyl)pyridazine-3-carboxamide

To a solution of 1B (6 mg, 0.013 mmol) in methanol (3 mL) was added NaOH(1.04 mg, 0.026 mmol) The mixture was heated to 40° C. for 2 hrs. Whenreaction completed, filtered, filtrate was removed in vacuo,chromatography (PE/EtOAc=50/50 then DCM/MeOH=97/3) to give the desiredproduct Example 1 (3 mg, yield: 50%) as a yellow solid. LM-MS: m/z=428.2[M+H]⁺. 1H NMR (400 MHz, DMSO) δ 10.91 (s, 1H), 9.14 (s, 1H), 8.56 (s,1H), 8.29 (s, 1H), 7.63 (dd, 1H), 7.53 (dd, 1H), 7.43 (s, 1H), 7.25 (t,1H), 4.17-4.12 (m, 2H), 3.95 (s, 3H), 3.74 (s, 3H), 3.49-3.37 (m, 2H).

Example 2:4-[2-methoxy-3-(1-methyl-1,2,4-triazol-3-yl)-anilino]-6-(3-methyl-2-oxo-imidazolidin-1-yl)-N-(trideuteriomethyl)pyridazine-3-carboxamide

To a solution of intermediate 1 (60 mg, 0.16 mmol) and 2A (32 mg, 0.32mmol) in 1,4-dioxane (8 mL) was added Cesium carbonate (100 mg, 0.32mmol), Pd₂(dba)₃ (43 mg, 0.048 mmol), and xantphos (46 mg, 0.08 mmol).The mixture degassed by N₂ for 3 times and heated to 120° C. for 4 hrs.When reaction completed, filtered, filtrate was removed in vacuo,chromatography (PE/EtOAc=50/50 then DCM/MeOH=97/3) to give the desiredproduct 2. (6 mg, yield: 9%) as a yellow solid. LM-MS: m/z=441.2 [M+H]⁺.¹H NMR (400 MHz, CDCl₃) δ 11.60 (s, 1H), 8.39 (s, 1H), 8.22 (s, 1H),8.06-7.88 (m, 2H), 7.50 (d, 1H), 7.32 (t, 1H), 4.62-4.49 (m, 2H), 4.03(s, 3H), 3.81 (s, 3H), 3.65-3.54 (m, 2H), 2.91 (s, 3H).

Example 3:4-[2-methoxy-3-(1-methyl-1,2,4-triazol-3-yl)anilino]-N-methyl-6-(2-oxoazetidin-1-yl)pyridazine-3-carboxamide

Intermediate 1 (0.05 g, 0.133 mmol), azetidin-2-one (0.02 g, 0.282mmol), cesium carbonate (0.086 g, 0.264 mmol),tris(dibenzylideneacetone)dipalladium (0.012 g, 0.013 mmoL) and xantphos(0.012 g, 0.021 mmol) were added to 45 mL sealed tube. 10 mL 1,4-dioxanewas added to the mixture. The resulting solution was stirred at 130° C.for 1 h under N₂ atmosphere. The mixture solution was evaporated todryness, residues was purified by flash chromatography to afford 3(0.0121 g, 20%) as a light yellow solid. ¹H NMR (400 MHz, CD₃OD) δ 8.70(s, 1H), 7.77 (d, J=7.6 Hz, 1H), 7.64-7.55 (m, 2H), 7.34 (t, J=8.0 Hz,1H), 4.05 (s, 3H), 3.92 (t, J=4.9 Hz, 2H), 3.75 (s, 3H), 3.25 (t, J=4.8Hz, 2H). LC-MS (ESI): m/z=412.2 [M+H]⁺.

Example 4:4-[2-methoxy-3-(1-methyl-1,2,4-triazol-3-yl)anilino]-6-(4-oxo-5-azaspiro[2.4]heptan-5-yl)-N-(trideuteriomethyl)pyridazine-3-carboxamide

To a solution of intermediate 1 (60 mg, 0.16 mmol) and 4A (35 mg, 0.32mmol) in 1,4-dioxane (8 mL) was added Cesium carbonate (100 mg, 0.32mmol), Pd₂(dba)₃ (43 mg, 0.048 mmol), and xantphos (46 mg, 0.08 mmol).The mixture degassed by N₂ for 3 times and heated to 110° C. for 4 hrs.When reaction completed, filtered, filtrate was removed in vacuo, Theresidue was purified by flash Chromatography (PE/EtOAc=50/50 thenDCM/MeOH=97/3) to afford the title compound Example 4 (24 mg, 33.33%) asa white solid. LM-MS: m/z=452.3 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 11.22(s, 1H), 8.53 (s, 1H), 8.32 (s, 1H), 8.16 (s, 1H), 7.78 (d, 1H), 7.55(d, 1H), 7.31 (t, 1H), 4.34 (t, 2H), 4.05 (s, 3H), 3.78 (s, 3H), 2.26(t, 2H), 1.28-1.24 (m, 2H), 0.98-0.93 (m, 2H).

Example 5:6-(3-cyclopropyl-2-oxo-imidazolidin-1-yl)-4-[2-methoxy-3-(1-methyl-1,2,4-triazol-3-yl)anilino]-N-(trideuteriomethyl)pyridazine-3-carboxamide

Step 1: 1-(2-chloroethyl)-3-cyclopropyl-urea

To a solution of cyclopropanamine (2.0 g, 35.03 mmol) in Acetonitrile(20 mL) was added 1-chloro-2-isocyanato-ethane (3.70 g, 35.03 mmol),then it was stirred at room temperature for 2 h. solid precipitation,filtered, give the desired product 5B (4.05 g, 71.1%) as a white solid,it was used in the next step without further purification. LM-MS:m/z=163.2 [M+H]⁺

Step 2: 1-cyclopropylimidazolidin-2-one

To a solution of 5B (0.5 g, 3.07 mmol) in THF (30 ml) was added sodiumhydride (0.15 g, 6.0 mmol), then it was stirred at room temperature for2h. Quenched with water (20 mL) and extracted by EtOAc (30 mL×2). Thecombined organic layers were washed by brine (30 mL), dried over Na₂SO₄,filtered and concentrated under reduced pressure to afford the crudeproduct which was purified by column chromatography (EtOAc/PE=1/1) togive the desired product 5C (0.17 g, yield: 38.67%) as a white solid.LM-MS: m/z=127.2 [M+H]⁺

Step 3:6-(3-cyclopropyl-2-oxo-imidazolidin-1-yl)-4-[2-methoxy-3-(1-methyl-1,2,4-triazol-3-yl)anilino]-N-(trideuteriomethyl)pyridazine-3-carboxamide

To a solution of intermediate 1 (70 mg, 0.18 mmol) and 5C (35 mg, 0.28mmol) in 1,4-dioxane (8 mL) was added Cesium carbonate (100 mg, 0.32mmol), Pd₂(dba)₃ (43 mg, 0.048 mmol), and xantphos (46 mg, 0.08 mmol).The mixture degassed by N₂ for 3 times and heated to 120° C. for 4 hrs.When reaction completed, filtered, filtrate was removed in vacuo,chromatography (PE/EtOAc=50/50 then DCM/MeOH=97/3) to give the desiredproduct Example 5 (10 mg, yield: 10%) as a yellow solid. LM-MS:m/z=467.2 [M+H]⁺. ¹H NMR (400 MHz, MeOD) δ 8.46 (s, 1H), 8.39 (s, 1H),7.66-7.62 (m, 2H), 7.24 (t, 1H), 4.11 (t, 2H), 4.02 (s, 3H), 3.74 (s,3H), 3.53 (t, 2H), 2.56-2.52 (m, 1H), 0.77-0.72 (m, 4H).

Example 6 :6-(3-isopropyl-2-oxo-imidazolidin-1-yl)-4-[2-methoxy-3-(1-methyl-1,2,4-triazol-3-yl)anilino]-N-(trideuteriomethyl)pyridazine-3-carboxamide

Step 1: 1-(2-chloroethyl)-3-isopropyl-urea

To a solution of propan-2-amine (2.0 g, 33.8 mmol) in Acetonitrile (20mL) was added 1-chloro-2-isocyanato-ethane (3.57 g, 33.8 mmol), then itwas stirred at room temperature for 2 h. solid precipitation, filtered,give the desired product Example 6B (4.2 g, 75.4%) as a white solid, itwas used in the next step without further purification. LM-MS: m/z=165.2[M+H]⁺. 1H NMR (400 MHz, CDCl₃) δ 5.39-4.32 (m, 2H), 3.85 (dt, 1H),3.65-3.58 (m, 2H), 3.58-3.49 (m, 2H), 1.15 (d, 6H).

Step 2: 1-isopropylimidazolidin-2-one

To a solution of 6B (0.5 g, 3.0 mmol) in THF (30 ml) was added sodiumhydride (0.15 g, 6.0 mmol), then it was stirred at room temperature for2 h. Quenched with water (20 mL) and extracted by EtOAc (30 mL×2). Thecombined organic layers were washed by brine (30 mL), dried over Na₂SO₄,filtered and concentrated under reduced pressure to afford the crudeproduct which was purified by column chromatography (EtOAc/PE=1/1) togive the desired product Example 6C (0.17 g, yield: 44%) as a whitesolid. LM-MS: m/z=129.2 [M+H]⁺. 1H NMR (400 MHz, CDCl₃) δ 4.36 (s, 1H),4.14 (dt, 1H), 3.42-3.33 (m, 4H), 1.14 (d, 3H), 1.12 (s, 3H).

Step 3:6-(3-isopropyl-2-oxo-imidazolidin-1-yl)-4-[2-methoxy-3-(1-methyl-1,2,4-triazol-3-yl)anilino]-N-(trideuteriomethyl)pyridazine-3-carboxamide;2,2,2-trifluoroaceticacid

To a solution of Intermediate 1 (60 mg, 0.16 mmol) and 6C (41 mg, 0.32mmol) in 1,4-dioxane (8 mL) was added Cesium carbonate (100 mg, 0.32mmol), Pd₂(dba)₃ (43 mg, 0.048 mmol), and xantphos (46 mg, 0.08 mmol).The mixture degassed by N₂ for 3 times and heated to 120° C. for 4 hrs.When reaction completed, filtered, filtrate was removed in vacuo,chromatography (PE/EtOAc=50/50 then DCM/MeOH=97/3) to give the desiredproduct Example 6 (5 mg, yield: 5%) as a yellow solid. LM-MS: m/z=469.2[M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 11.47 (s, 1H), 8.54 (s, 1H), 8.02 (s,1H), 7.89 (s, 1H), 7.83 (d, 1H), 7.54 (d, 1H), 7.34 (t, 1H), 4.21 (dd,3H), 4.06 (s, 3H), 3.76 (s, 3H), 3.64-3.49 (m, 2H), 1.19 (d, 6H).

Example 7:6-(3,3-dimethyl-2-oxo-pyrrolidin-1-yl)-4-[2-methoxy-3-(1-methyl-1,2,4-triazol-3-yl)anilino]-N-(trideuteriomethyl)pyridazine-3-carboxamide

To a solution of intermediate 1 (60 mg, 0.16 mmol) and 7A (36 mg, 0.32mmol) in 1,4-dioxane (8 mL) was added Cesium carbonate (100 mg, 0.32mmol), Pd₂(dba)₃ (43 mg, 0.048 mmol), and xantphos (46 mg, 0.08 mmol).The mixture degassed by N₂ for 3 times and heated to 120° C. for 4 hrs.When reaction completed, filtered, filtrate was removed in vacuo,chromatography (PE/EtOAc=50/50 then DCM/MeOH=97/3) to give the desiredproduct Example 7 (24 mg, yield: 30%) as a yellow solid. LM-MS:m/z=455.3 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 11.08 (s, 1H), 8.42 (d, 2H),8.17 (s, 1H), 7.77 (d, 1H), 7.58 (d, 1H), 7.31 (t, 1H), 4.17 (t, 2H),4.04 (s, 3H), 3.80 (s, 3H), 2.02 (t, 2H), 1.25 (s, 6H).

Example 8:6-[3-(2,2-difluoroethyl)-2-oxo-imidazolidin-1-yl]-4-[2-methoxy-3-(1-methyl-1,2,4-triazol-3-yl)anilino]-N-(trideuteriomethyl)pyridazine-3-carboxamide;2,2,2-trifluoroaceticacid

Step 1: 1-(2-chloroethyl)-3-(2,2-difluoroethyl)urea

To a solution of 2,2-difluoroethanamine (2.0 g, 24.67 mmol) inAcetonitrile (20 mL) was added 1-chloro-2-isocyanato-ethane (2.60 g,24.67 mmol), then it was stirred at room temperature for 2 h. solidprecipitation, filtered, give the desired product 8B (2.80 g, 60.83%) asa white solid, it was used in the next step without furtherpurification. LM-MS: m/z=187.2 [M+H]⁺

Step 2: 1-(2,2-difluoroethyl)imidazolidin-2-one

To a solution of 8B (0.5 g, 2.68 mmol) in THF (30 ml) was added sodiumhydride (0.15 g, 6.0 mmol), then it was stirred at room temperature for2 h. Quenched with water (20 mL) and extracted by EtOAc (30 mL×2). Thecombined organic layers were washed by brine (30 mL), dried over Na₂SO₄,filtered and concentrated under reduced pressure to afford the crudeproduct which was purified by column chromatography (EtOAc/PE=1/1) togive the desired product 8C (0.15 g, yield: 37.29%) as a white solid.LM-MS: m/z=151.2 [M+H]⁺

Step 3:6-[3-(2,2-difluoroethyl)-2-oxo-imidazolidin-1-yl]-4-[2-methoxy-3-(1-methyl-1,2,4-triazol-3-yl)anilino]-N-(trideuteriomethyl)pyridazine-3-carboxamide;2,2,2-trifluoroaceticacid

To a solution of intermediate 1 (80 mg, 0.21 mmol) and 8C (47 mg, 0.32mmol) in 1,4-dioxane (8 mL) was added Cesium carbonate (100 mg, 0.32mmol), Pd₂(dba)₃ (43 mg, 0.048 mmol), and xantphos (46 mg, 0.08 mmol).The mixture degassed by N₂ for 3 times and heated to 120° C. for 4 hrs.When reaction completed, filtered, filtrate was removed in vacuo,chromatography (PE/EtOAc=50/50 then DCM/MeOH=97/3) to give the desiredproduct Example 8. (4 mg, yield: 4%) as a yellow solid. LM-MS: m/z=491.2[M+H]⁺. ¹H NMR (400 MHz, CD₃OD): δ 7.77-7.71 (m, 2H), 7.64 (d, 1H), 7.33(t, 1H), 6.18-5.91 (m, 1H), 4.09 (t, 1H), 4.04 (s, 3H), 3.72-3.72 (m,4H), 3.70-3.65 (m, 2H).

Example 9:6-[3-(2-methoxyethyl)-2-oxo-imidazolidin-1-yl]-4-[2-methoxy-3-(1-methyl-1,2,4-triazol-3-yl)anilino]-N-(trideuteriomethyl)pyridazine-3-carboxamide

Step 1: 1-(2-chloroethyl)-3-(2-methoxyethyl)urea

To a solution of 2-methoxyethanamine (0.38 g, 5 mmol) in THF (10 mL) wasadded 1-chloro-2-isocyanato-ethane (0.53 g, 5 mmol), then it was stirredat room temperature for 2 h give the desired product 9B (0.81 g, 90%) asa colorless oil, it was used in the next step without furtherpurification. LC-MS: m/z=180.6 [M+H]⁺

Step 2: 1-(3-methyloxetan-3-yl)imidazolidin-2-one

To a solution of 9B (0.81 g, 4.5 mmol) in THF (20 ml) was added sodiumhydride (0.13 g, 5.4 mmol), then it was stirred at room temperature for4 h. Quenched with water (20 mL) and extracted by EtOAc (40 mL×2). Thecombined organic layers were washed by brine (60 mL), dried over Na₂SO₄,filtered and concentrated under reduced pressure to afford the crudeproduct which was purified by column chromatography (EtOAc/PE=1/1) togive the desired product 9C (0.25 g, yield: 40%) as a colorless oil.LC-MS: m/z=144.2 [M+H]⁺

Step 3:6-[3-(2-methoxyethyl)-2-oxo-imidazolidin-1-yl]-4-[2-methoxy-3-(1-methyl-1,2,4-triazol-3-yl)anilino]-N-(trideuteriomethyl)pyridazine-3-carboxamide

To a solution of intermediate 1 (60 mg, 0.16 mmol) and 9C (30 mg, 0.2mmol) in 1,4-dioxane (8 mL) was added Cesium carbonate (160 mg, 0.5mmol), Pd₂(dba)₃ (20 mg, 0.02 mmol), and xantphos (24 mg, 0.04 mmol).The mixture degassed by N₂ for 3 times and heated to 130° C. for 2 hrs.When reaction completed, filtered, filtrate was removed in vacuo,chromatography (PE/EtOAc=50/50 then DCM/MeOH=95/5) to give the desiredproduct Example 9 (8.4 mg, yield: 11%) as a white solid. LM-MS:m/z=484.5 [M+H]⁺ ¹H NMR (400 MHz, CDCl₃): δ 11.03 (s, 1H), 8.36 (s, 1H),8.13-8.11 (m, 2H), 7.80-7.79 (d, 1H), 7.55-7.53 (d, 1H), 7.25-7.29 (m,1H), 4.30-4.26 (q, 2H), 4.00 (s, 3H), 3.82 (s, 3H), 3.68-3.64 (q, 2H),3.56-3.53 (q, 2H), 3.49-3.46 (q, 2H), 3.35 (s, 3H).

Example 10:6-[3-(3,3-difluorocyclobutyl)-2-oxo-imidazolidin-1-yl]-4-[2-methoxy-3-(1-methyl-1,2,4-triazol-3-yl)anilino]-N-(trideuteriomethyl)pyridazine-3-carboxamide

Step 1: 1-(2-chloroethyl)-3-(3,3-difluorocyclobutyl)urea

To a solution of 3,3-difluorocyclobutanamine hydrochloride (10A) (1.0 g,6.96 mmol) and TEA (1.94 mL, 13.93 mmol) in THF (15 mL) was added1-chloro-2-isocyanato-ethane (0.6 mL, 6.96 mmol) via a syringe, then itwas stirred at room temperature for 2 h. The mixture solution wasevaporated to dryness, redissolved in EtOAc (80 mL). The organic layerwas then washed with NaHCO₃ and brine, dried over Na₂SO₄, filtered andconcentrated, then the title compound 10B (550 mg, 37.4%) was obtainedas white solid, which was used in the next step without furtherpurification. LM-MS: m/z=213.1 [M+H]⁺

Step 2: 1-(3,3-difluorocyclobutyl)amidazolidin-2-one

To a solution of 10B (0.5 g, 2.35 mmol) in THF (30 mL) was added sodiumhydride (0.19 g, 4.7 mmol), then it was stirred at room temperature for2 h. Quenched with water (20 mL) and extracted by EtOAc (30 mL×2). Thecombined organic layers were washed by brine (30 mL), dried over Na₂SO₄,filtered and concentrated under reduced pressure to afford the crudeproduct which was purified by column chromatography (EtOAc/PE=1/1) togive the desired product 10C (0.23 g, yield: 55.4%) as a white solid.

Step 3:6-[3-(3,3-difluorocyclobutyl)-2-oxo-imidazolidin-1-yl]-4-[2-methoxy-3-(1-methyl-1,2,4-triazol-3-yl)anilino]-N-(trideuteriomethyl)pyridazine-3-carboxamide

To a solution of intermediate 1 (60 mg, 0.16 mmol) and 10C (56 mg, 0.32mmol) in 1,4-dioxane (8 mL) was added Cesium carbonate (100 mg, 0.32mmol), Pd₂(dba)₃ (43 mg, 0.048 mmol), and xantphos (46 mg, 0.08 mmol).The mixture degassed by N₂ for 3 times and heated to 110° C. for 4 hrs.When reaction completed, filtered, filtrate was removed in vacuo. Theresidue was purified by flash Chromatography

(PE/EtOAc=50/50 then DCM/MeOH=97/3) to afford the title compound Example10 (12 mg, yield: 13.95%) as a white solid. LM-MS: m/z=517.2 [M+H]⁺. ¹HNMR (400 MHz, CDCl₃): δ 10.98 (s, 1H), 8.32 (s, 1H), 8.18-8.07 (m, 2H),7.77 (d, 1H), 7.55-7.49 (d, 1H), 7.30 (d, 1H), 4.51-4.41 (m, 1H), 4.26(t, 2H), 4.03 (s, 3H), 3.78 (s, 3H), 3.60 (t, 2H), 2.95-2.71 (m, 4H).

Example 11:6-(3-cyclobutyl-2-oxo-imidazolidin-1-yl)-4-[2-methoxy-3-(1-methyl-1,2,4-triazol-3-yl)anilino]-N-(trideuteriomethyl)pyridazine-3-carboxamide

Step 1: 1-(2-chloroethyl)-3-cyclobutyl-urea

To a solution of cyclobutanamine (1.0 g, 14.1 mmol) in acetonitrile (20mL) was added 1-chloro-2-isocyanato-ethane (1.48 g, 14.1 mmol), then itwas stirred at room temperature for 2 h. solid precipitation, filtered,give the desired product Example 11B (1.5 g, 60.4%) as a white solid, itwas used in the next step without further purification. LM-MS: m/z=177.1[M+H]⁺. ¹H NMR (400 MHz, CDCl₃): δ 4.57 (s, 2H), 4.16-4.06 (m, 1H),3.68-3.59 (m, 2H), 3.59- 3.51 (m, 2H), 2.40-2.30 (m, 2H), 1.91-1.79 (m,2H), 1.79-1.60 (m, 2H).

Step 2: 1-cyclobutylimidazolidin-2-one

To a solution of 1-(2-chloroethyl)-3-cyclobutyl-urea (1.0 g, 5.7 mmol)in THF (30 ml) was added sodium hydride (0.27 g, 11 mmol), then it wasstirred at room temperature for 2 h. Quenched with water (20 mL) andextracted by EtOAc (30 mL×2). The combined organic layers were washed bybrine (30 mL), dried over Na₂SO₄, filtered and concentrated underreduced pressure to afford the crude product which was purified bycolumn chromatography (EtOAc/PE=1/1) to give the desired product Example11C (0.70 g, yield: 88%) as a white solid. LM-MS: m/z=141.2 [M+H]⁺. ¹HNMR (400 MHz, CDCl₃) δ 4.43 (t, 1H), 3.50 (dd, 2H), 3.40 (dd, 2H),2.14-2.05 (m, 4H), 1.68-1.61 (m, 2H).

Step 3:6-(3-cyclobutyl-2-oxo-imidazolidin-1-yl)-4-[2-methoxy-3-(1-methyl-1,2,4-triazol-3-yl)anilino]-N-(trideuteriomethyl)pyridazine-3-carboxamide

To a solution of Intermediate 1 (60 mg, 0.16 mmol) and 11C (45 mg, 0.32mmol) in 1,4-dioxane (8 mL) was added Cesium carbonate (100 mg, 0.32mmol), Pd₂(dba)₃ (43 mg, 0.048 mmol), and xantphos (46 mg, 0.08 mmol).The mixture degassed by N₂ for 3 times and heated to 120° C. for 4 hrs.When reaction completed, filtered, filtrate was removed in vacuo,chromatography (PE/EtOAc=50/50 then DCM/MeOH=97/3) to give the desiredproduct 11 (5 mg, yield: 7%) as a yellow solid. LM-MS: m/z=481.2 [M+H]⁺.¹H NMR (400 MHz, CD₃OD) δ 8.46 (s, 1H), 8.37 (s, 1H), 7.63 (td, 2H),7.29 (t, 1H), 4.43 (t, 1H), 4.19-4.09 (m, 2H), 4.01 (s, 3H), 3.74 (s,3H), 3.70-3.61 (m, 2H), 2.38-2.23 (m, 2H), 2.13 (dd, 2H), 1.77-1.68 (m,2H).

Example 12:6-(3-ethyl-2-oxo-imidazolidin-1-yl)-4-[2-methoxy-3(1-methyl-1,2,4-triazol-3-yl)anilino]-N-(trideuteriomethyl)pyridazine-3-carboxamide

Step 1: 1-(2-chloroethyl)-3-ethyl-urea

To a solution of ethylamine hydrochloride (1.0 g, 12.3 mmol) inAcetonitrile (20 mL) was added Triethylamine (2.48 g, 24.6 mmol) and1-chloro-2-isocyanato-ethane (1.24 g, 12.3 mmol) , then it was stirredat room temperature for 2 h. solid precipitation, filtered, give thedesired product Example 12B (1.5 g, 81%) as a white solid, it was usedin the next step without further purification.

Step 2: 1-ethylimidazolidin-2-one

To a solution of 12B (1.0 g, 6.6 mmol) in THF (30 ml) was added sodiumhydride (0.32 g, 13 mmol), then it was stirred at room temperature for 2h. Quenched with water (20 mL) and extracted by EtOAc (30 mL×2). Thecombined organic layers were washed by brine (30 mL), dried over Na₂SO₄,filtered and concentrated under reduced pressure to afford the crudeproduct which was purified by column chromatography (EtOAc/PE=1/1) togive the desired product Example 12C (0.70 g, yield: 92%) as a whitesolid.

Step 3:6-(3-ethyl-2-oxo-imidazolidin-1-yl)-4-[2-methoxy-3-(1-methyl-1,2,4-triazol-3-yl)anilino]-N-(trideuteriomethyl)pyridazine--3-carboxamide

To a solution of Intermediate 1 (60 mg, 0.16 mmol) and 12C (36 mg, 0.32mmol) in 1,4-dioxane (8 mL) was added Cesium carbonate (100 mg, 0.32mmol), Pd₂(dba)₃ (43 mg, 0.048 mmol), and xantphos (46 mg, 0.08 mmol).The mixture degassed by N₂ for 3 times and heated to 120° C. for 4 hrs.When reaction completed, filtered, filtrate was removed in vacuo,chromatography (PE/EtOAc=50/50 then DCM/MeOH=97/3) to give the desiredproduct Example 12 (5 mg, yield: 6%) as a yellow solid. LM-MS: m/z=455.3[M+H]⁺. ¹H NMR (400 MHz, MeOD): δ 8.53 (s, 1H), 7.76 (dd, 1H), 7.63 (dd,1H), 7.58 (s, 1H), 7.35 (d, 1H), 4.13-3.94 (m, 5H), 3.74 (s, 3H),3.69-3.58 (m, 2H), 3.37 (d, 2H), 1.19 (t, 3H).

Example 13:6-(3-isopropyl-2-oxo-imidazolidin-1-yl)-4-[2-methoxy-3-(1-methyl-1,2,4-triazol-3-yl)anilino]-N-(trideuteriomethyl)pyridazine-3-carboxamide

Step 1:1-(2-chloroethyl)-3-[2,2,2-trideuterio-1-(trideuteriomethyl)ethyl]urea

To a solution of 1,1,1,3,3,3-hexadeuteriopropan-2-amine (0.20 g, 3.1mmol) in acetonitrile (20 mL) was added 1-chloro-2-isocyanato-ethane(0.32 g, 3.1 mmol), then it was stirred at room temperature for 2 h.solid precipitation, filtered, give the desired product 13B (0.4 g, 76%)as a white solid, it was used in the next step without furtherpurification. LM-MS: m/z=171.2 [M+H]⁺

Step 2:1-[2,2,2-trideuterio-1-(trideuteriomethyl)ethyl]imidazolidin-2-one

To a solution of 13B (0.2 g, 1.2 mmol) in THF (10 ml) was added sodiumhydride (0.056 g, 2.4 mmol), then it was stirred at room temperature for2 h. Quenched with water (20 mL) and extracted by EtOAc (30 mL×2). Thecombined organic layers were washed by brine (30 mL), dried over Na₂SO₄,filtered and concentrated under reduced pressure to afford the crudeproduct which was purified by column chromatography (EtOAc/PE=1/1) togive the desired product Example 13C (0.070 g, yield: 40%) as a whitesolid.

Step 3:6-(3-isopropyl-2-oxo-imidazolidin-1-yl)-4-[2-methoxy-3-(1-methyl-1,2,4-triazol-3-yl)anilino]-N-(trideuteriomethyl)pyridazine-3-carboxamide

To a solution of intermediate 1 (80 mg, 0.21 mmol) and 13C (57 mg, 0.42mmol) in 1,4-dioxane (8 mL) was added Cesium carbonate (140 mg, 0.42mmol), Pd₂(dba)₃ (57 mg, 0.063 mmol), and xantphos (72 mg, 0.126 mmol).The mixture degassed by N₂ for 3 times and heated to 120° C. for 4 hrs.When reaction completed, filtered, filtrate was removed in vacuo,chromatography (PE/EtOAc=50/50 then DCM/MeOH=97/3) to give the desiredproduct Example 13 (7 mg, yield: 7%) as a yellow solid. LM-MS: m/z=475.3[M+H]⁺. ¹ H NMR (400 MHz, MeOD): δ 8.46 (s, 1H), 8.40 (d, 1H), 7.66-7.61(m, 2H), 7.29 (t, 1H), 4.14 (dd, 3H), 4.01 (s, 3H), 3.74 (s, 3H),3.58-3.52 (m, 2H).

Example 14:6-(3-isopropyl-2-oxo-imidazolidin-1-yl)-4-[3-(1-methyl-1,2,4-triazol-3-yl)-2-(trideuteriomethoxy)anilino]-N-(trideuteriomethyl)pyridazine-3-carboxamide

To a solution of intermediate 3 (160 mg, 0.42 mmol) and1-isopropylimidazolidin-2-one (110 mg, 0.84 mmol) in 1,4-dioxane (8 mL)was added Cesium carbonate (270 mg, 0.84 mmol), Pd₂(dba)₃ (115.3 mg,0.126 mmol), and xantphos (145.6 mg, 0.252 mmol). The mixture degassedby N₂ for 3 times and heated to 120° C. for 4 hrs. When reactioncompleted, filtered, filtrate was removed in vacuo, chromatography(PE/EtOAc=50/50 then DCM/MeOH=97/3) to give the desired product Example14 (60 mg, yield: 24%) as a yellow solid. LM-MS: m/z=472.3 [M+H]⁺. ¹HNMR (400 MHz, CDCl₃) δ 11.10 (s, 1H), 8.38 (s, 1H), 8.10 (d, 2H), 7.81(d, 1H), 7.55 (d, 1H), 7.29 (d, 1H), 4.31 (s, 2H), 4.27-4.21 (m, 1H),4.00 (s, 3H), 3.53-3.46 (m, 2H), 1.18 (d, 6H).

Example 15:6-(3-isopropyl-2-oxo-imidazolidin-1-yl)-4-[2-methoxy-3-[1-(trideuteriomethyl)-1,2,4-triazol-3-yl]anilino]-N-(trideuteriomethyl)pyridazine-3-carboxamide

To a solution of Intermediate 2 (60 mg, 0.16 mmol) and1-isopropylimidazolidin-2-one (41 mg, 0.32 mmol) in 1,4-dioxane (8 mL)was added Cesium carbonate (100 mg, 0.32 mmol), Pd₂(dba)₃ (43 mg, 0.048mmol), and xantphos (46 mg, 0.08 mmol). The mixture degassed by N₂ for 3times and heated to 120° C. for 4 hrs. When reaction completed,filtered, filtrate was removed in vacuo, chromatography (PE/EtOAc=50/50then DCM/MeOH=97/3) to give the desired product Example 15. (6 mg,yield: 8%) as a yellow solid. LM-MS: m/z=472.3 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃) δ 10.92 (s, 1H), 8.35 (s, 1H), 8.16 (s, 1H), 8.10 (s, 1H), 7.77(dd, 1H), 7.55 (dd, 1H), 7.28 (d, 1H), 4.25 (ddd, 3H), 3.81 (s, 3H),3.51-3.44 (m, 2H), 1.18 (d, 6H).

Example 16.4-[2-methoxy-3-(1-methyl-1,2,4-triazol-3-yl)anilino]-6-[3-(3-methyloxetan-3-yl)-2-oxo-imidazolidin-1-yl]-N-(trideuteriomethyl)pyridazine-3-carboxamide

Step 1: 1-(2-chloroethyl)-3-(3-methyloxetan-3-yl)urea

To a solution of 3-methyloxetan-3-amine (0.87 g, 10 mmol) in THF (20 mL)was added 1-chloro-2-isocyanato-ethane (1.06 g, 10 mmol), then it wasstirred at room temperature for 2 h give the desired product 168 (1.82g, 94%) as a colorless oil, it was used in the next step without furtherpurification. LC-MS: m/z=192.6 [M+H]⁺

Step 2: 1-(3-methyloxetan-3-yl)imidazolidin-2-one

To a solution of 168 (1.82 g, 9.2 mmol) in THF (30 ml) was added sodiumhydride (0.29 g, 12 mmol), then it was stirred at room temperature for 4h. Quenched with water (20 mL) and extracted by EtOAc (40 mL×2). Thecombined organic layers were washed by brine (60 mL), dried over Na₂SO₄,filtered and concentrated under reduced pressure to afford the crudeproduct which was purified by column chromatography (EtOAc/PE=1/1) togive the desired product 16C (1.0 g, yield: 69%) as a white solid.LC-MS: m/z=156.2 [M+H]⁺

Step 3:4-[2-methoxy-3-(1-methyl-1,2,4-triazol-3-yl)anilino]-6-[3-(3-methyloxetan-3-yl)-2-oxo-imidazolidin-1-yl]-N-(trideuteriomethyl)pyridazine-3-carboxamide

To a solution of intermediate 1 (110 mg, 0.3 mmol) and 16C (63 mg, 0.4mmol) in 1,4-dioxane (8 mL) was added Cesium carbonate (300 mg, 0.9mmol), Pd₂(dba)₃(30 mg, 0.03 mmol), and xantphos (35 mg, 0.06 mmol). Themixture degassed by N₂ for 3 times and heated to 130° C. for 2 hrs. Whenreaction completed, filtered, filtrate was removed in vacuo,chromatography (PE/EtOAc=50/50 then DCM/MeOH=95/5) to give the desiredproduct Example 16. (40 mg, yield: 30%) as a white solid. LM-MS:m/z=496.6 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): δ 11.09 (s, 1H), 8.13-8.06(m, 3H), 7.76 (s, 1H), 7.45 (s, 1H), 7.19 (m, 1H), 4.83-4.81 (d, 2H),4.35-4.30 (m, 4H), 3.94 (s, 3H), 3.75 (s, 3H), 3.39 (m, 2H), 1.57 (s,3H)

Example 17:6-(3-isobutyl-2-oxo-imidazolidin-1-yl)-4-[2-methoxy-3-(1-methyl-1,2,4-triazol-3-yl)anilino]-N-(trideuteriomethyl)pyridazine-3-carboxamide

Step 1: 1-(2-chloroethyl)-3-isobutyl-urea

To a solution of 2-methylpropan-1-amine (1.0 g, 14 mmol) in acetonitrile(20 mL) was added 1-chloro-2-isocyanato-ethane (1.4 g, 14 mmol), then itwas stirred at room temperature for 2 h. solid precipitation, filtered,give the desired product Example 17B (1.5 g, 61%) as a white solid, itwas used in the next step without further purification. LM-MS: m/z=171.2[M+H]⁺

Step 2: 1-(2-chloroethyl)-3-isobutyl-urea

To a solution of 1-(2-chloroethyl)-3-isobutyl-urea (1.2 g, 6.7 mmol) inTHF (10 ml) was added sodium hydride (0.32 g, 13 mmol), then it wasstirred at room temperature for 2 h. Quenched with water (20 mL) andextracted by EtOAc (30 mL×2). The combined organic layers were washed bybrine (30 mL), dried over Na₂SO₄, filtered and concentrated underreduced pressure to afford the crude product which was purified bycolumn chromatography (EtOAc/PE=1/1) to give the desired product Example17C (0.5 g, yield: 50%) as a white solid.

Step 3: 6-(3-isobutyl-2-oxo-imidazolidin-1-yl)-4-[2-methoxy-3-(1-methyl-1,2,4-triazol-3-yl)anilino]-N-(trideuteriomethyl)pyridazine-3-carboxamide

To a solution of intermediate 1 (110 mg, 0.292 mmol) and1-(2-chloroethyl)-3-isobutyl-urea (83 mg, 0.584 mmol) in 1,4-dioxane (8mL) was added Cesium carbonate (190 mg, 0.584 mmol), Pd₂(dba)₃ (80 mg,0.087 mmol), and xantphos (100.7 mg, 0.175 mmol). The mixture degassedby N₂ for 3 times and heated to 120° C. for 4 hrs. When reactioncompleted, filtered, filtrate was removed in vacuo, chromatography(PE/EtOAc=50/50 then DCM/MeOH=97/3) to give the desired product Example17 (55 mg, yield: 39%) as a yellow solid. LM-MS: m/z=483.3 [M+H]⁺. ¹HNMR (400 MHz, CDCl₃) δ 11.01 (s, 1H), 8.37 (s, 1H), 8.11 (d, 2H), 7.78(d, 1H), 7.56 (d, 1H), 7.28 (d, 1H), 4.34-4.21 (m, 2H), 4.00 (s, 3H),3.82 (s, 3H), 3.58-3.48 (m, 2H), 3.09 (d, 2H), 1.95-1.90 (m, 1H), 0.91(dd, 6H).

Example 18:6-(3-cyclopentyl-2-oxo-imidazolidin-1-yl)-4-[2-methoxy-3-(1-methyl-1,2,4-triazol-3-yl)anilino]-N-(trideuteriomethyl)pyridazine-3-carboxamide

Step 1: 1-(2-chloroethyl)-3-cyclopentyl-urea

To a solution of cyclopentylamine (18A) (1.0 g, 11.7 mmol) and in THF(15 mL) was added 1-chloro-2-isocyanato-ethane (1 mL, 11.7 mmol) via asyringe, then it was stirred at room temperature for 2 h. The mixturesolution was evaporated to afford the title compound 18B (780 mg,34.97%) as a colourless oil, which was used in the next step withoutfurther purification. LM-MS: m/z=191.1 [M+H]⁺

Step 2: 1-cyclopentylimidazolidin-2-one

To a solution of T177B (0.5 g, 2.63 mmol) in THF (30 mL) was addedsodium hydride (0.21 g, 5.26 mmol), then it was stirred at roomtemperature for 2 h. Quenched with water (20 mL) and extracted by EtOAc(30 mL×2). The combined organic layers were washed by brine (30 mL),dried over Na₂SO₄, filtered and concentrated under reduced pressure toafford the title product (18C) (310 mg, 76.54%) as colourless oil.LM-MS: m/z=155.2 [M+H]⁺

Step 3:6-(3-cyclopentyl-2-oxo-imidazolidin-1-yl)-4-yl)-4-[2-methoxy-3-(1-methyl-1,2,4-triazol-3-yl)anilino]-N-(trideuteriomethyl)pyridazine-3-carboxamide

To a solution of intermediate 1 (60 mg, 0.16 mmol) and 18C (49 mg, 0.32mmol) in 1,4-dioxane (8 mL) was added Cesium carbonate (100 mg, 0.32mmol), Pd₂(dba)₃ (43 mg, 0.048 mmol), and xantphos (46 mg, 0.08 mmol).The mixture degassed by N₂ for 3 times and heated to 110° C. for 4 hrs.When reaction completed, filtered, filtrate was removed in vacuo. Theresidue was purified by flash Chromatography (PE/EtOAc=50/50 thenDCM/MeOH=97/3) to afford the title compound Example 18 (16 mg, 20.3%) asa white solid. LM-MS: m/z=495.3 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 11.05(s, 1H), 8.37 (s, 1H), 8.14-8.08 (m, 2H), 7.80 (d, 1H), 7.55 (d, 1H),7.29 (d, 1H), 4.41-4.32 (m, 1H), 4.31-4.25 (m, 2H), 4.00 (s, 3H), 3.82(s, 3H), 3.57-3.45 (m, 2H), 1.88-1.82 (m, 2H), 1.74-1.69 (m, 2H),1.66-1.50 (m, 4H).

Example 19:6-[3-(3-bicyclo[1.1.1]pentanyl)-2-oxo-imidazolidin-1-yl]-4-[2-methoxy-3-(1-methyl-1,2,4-triazol-3-yl)anilino]-N-(trideuteriomethyl)pyridazine-3-carboxamide

Step 1: 1-(3-bicyclo[1.1.1]pentanyl)-3-(2-chloroethyl)urea

To a solution of bicyclo[1.1.1]pentan-3-amine (0.5 g, 4.2 mmol) inacetonitrile (20 mL) was added 1-chloro-2-isocyanato-ethane (0.44 g, 4.2mmol) then it was stirred at room temperature for 2 h. solidprecipitation, filtered, give the desired product Example 198 (0.5 g,63%) as a white solid, it was used in the next step without furtherpurification. LM-MS: m/z=189.1 [M+H]⁺

Step 2: 1-(3-bicyclo[1.1.1]pentanyl)imidazolidin-2-one

To a solution of 19B (0.5 g, 2.7 mmol) in THF (10 ml) was added sodiumhydride (0.13 g, 5.3 mmol), then it was stirred at room temperature for2 h. Quenched with water (20 mL) and extracted by EtOAc (30 mL×2). Thecombined organic layers were washed by brine (30 mL), dried over Na₂SO₄,filtered and concentrated under reduced pressure to afford the crudeproduct which was purified by column chromatography (EtOAc/PE=1/1) togive the desired product Example T202C (0.35 g, yield: 87%) as a whitesolid.

Step 3:6-[3-(3-bicyclo[1.1.1]pentanyl)-2-oxo-imidazolidin-1-yl]-4-[2-methoxy-3-(1-methyl-1,2,4-triazol-3-yl)anilino]-N-(trideuteriomethyl)pyridazine-3-carboxamide

To a solution of intermediate 1 (170 mg, 0.451 mmol) and 19C (103 mg,0.677 mmol) in 1,4-dioxane (8 mL) was added Cesium carbonate (293 mg,0.902 mmol), Pd₂(dba)₃ (123.8 mg, 0.135 mmol), and xantphos (155 mg,0.27 mmol). The mixture degassed by N₂ for 3 times and heated to 120° C.for 4 hrs. When reaction completed, filtered, filtrate was removed invacuo, chromatography (PE/EtOAc=50/50 then DCM/MeOH=97/3) to give thedesired product Example 19 (55 mg, yield: 39%) as a yellow solid. LM-MS:m/z=493.3 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): δ 10.94 (s, 1H), 8.30 (s,1H), 8.12 (d, 2H), 7.78 (dd, 1H), 7.54 (dd, 1H), 7.28 (d, 1H), 4.24-4.15(m, 2H), 4.00 (s, 3H), 3.81 (s, 3H), 3.57-3.46 (m, 2H), 2.48 (s, 1H),2.13 (s, 6H).

Example 20:6-(3-cyclobutyl-2-oxo-imidazolidin-1-yl)-4-[3-(1-methyl-1,2,4-triazol-3-yl)-2-(trideuteriomethoxy)anilino]-N-(trideuteriomethyl)pyridazine-3-carboxamide

To a solution of intermediate 3 (60 mg, 0.16 mmol) and 20C (45 mg, 0.32mmol) in 1,4-dioxane (8 mL) was added Cesium carbonate (100 mg, 0.32mmol), Pd₂(dba)₃ (43 mg, 0.048 mmol), and xantphos (46 mg, 0.08 mmol).The mixture degassed by N₂ for 3 times and heated to 120° C. for 4 hrs.When reaction completed, filtered, filtrate was removed in vacuo,chromatography (PE/EtOAc=50/50 then DCM/MeOH=97/3) to give the desiredproduct Example 20 (6 mg, yield: 8%) as a yellow solid. LM-MS: m/z=484.3[M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 10.85 (s, 1H), 8.34 (s, 1H), 8.11 (d,2H), 7.75 (dd, 1H), 7.55 (dd, 1H), 7.27 (d, 1H), 4.62-4.47 (m, 1H),4.27-4.11 (m, 2H), 3.99 (s, 3H), 3.65-3.52 (m, 2H), 2.26-2.03 (m, 4H),1.70 (dt, 2H).

Example 21:6-(3-isopropyl-2-oxo-imidazolidin-1-yl)-4-[2-methoxy-3-(1-methyl-1,2,4-triazol-3-yl)anilino]-N-(trideuteriomethyl)pyridazine-3-carboxamide

To a solution of intermediate 2 (200 mg, 0.527 mmol) and 21C (141 mg,1.05 mmol) in 1,4-dioxane (8 mL) was added Cesium carbonate (342 mg,1.05 mmol), Pd₂(dba)₃ (144.6 mg, 0.158 mmol), and xantphos (182.6 mg,0.316 mmol). The mixture degassed by N₂ for 3 times and heated to 120°C. for 4 hrs. When reaction completed, filtered, filtrate was removed invacuo, chromatography (PE/EtOAc=50/50 then DCM/MeOH=97/3) to give thedesired product Example 21 (60 mg, yield: 24%) as a yellow solid. LM-MS:m/z=478.3 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): δ 11.04-10.91 (m, 1H), 8.38(t, 1H), 8.15-8.03 (m, 2H), 7.82-7.75 (m, 1H), 7.60-7.52 (m, 1H),7.31-7.26 (m, 1H), 4.32-4.18 (m, 3H), 3.86-3.76 (m, 3H), 3.53-3.44 (m,2H).

Example 22:6-(3-cyclobutyl-2-oxo-imidazolidin-1-yl)-4-[2-methoxy-3-[1-(trideuteriomethyl)-1,2,4-triazol-3-yl]anilino]-N-(trideuteriomethyl)pyridazine-3-carboxamide

To a solution of intermediate 2 (60 mg, 0.16 mmol) and 22C (45 mg, 0.32mmol) in 1,4-dioxane (8 mL) was added Cesium carbonate (100 mg, 0.32mmol), Pd₂(dba)₃ (43 mg, 0.048 mmol), and xantphos (46 mg, 0.08 mmol).The mixture degassed by N₂ for 3 times and heated to 120° C. for 4 hrs.When reaction completed, filtered, filtrate was removed in vacuo,chromatography (PE/EtOAc=50/50 then DCM/MeOH=97/3) to give the desiredproduct Example 22. (6 mg, yield: 8%) as a yellow solid. LM-MS:m/z=484.3 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 10.97 (s, 1H), 8.35 (s, 1H),8.11 (d, 2H), 7.79 (dd, 1H), 7.54 (dt, 1H), 7.28 (d, 1H), 4.53 (t, 1H),4.29-4.21 (m, 2H), 3.81 (s, 3H), 3.66-3.53 (m, 2H), 2.25-2.07 (m, 4H),1.74-1.65 (m, 2H).

Example 23

Step 1: Example 23b

To a solution of dimethyl 3-oxopentanedioate (5.0 g, 28.7 mmol) andNi(acac)₂(738 mg, 2.87 mmol) in dioxane (30 mL) was added NH₂—CN (3.6 g,86.2 mmol). The mixture was stirred at 110° C. for o.n. The reaction wascooled to r.t. The mixture was filtered and the filter cake wascollected, washed with MeOH (20 mL) and concentrated in vacuo to givethe desired product Example 23b (3.0 g, 56.6% yield) as a yellow solid.LCMS [M+1]⁺=185.0

Step 2: Example 23c

To a solution of Example 23b (2.5 g, 13.58 mmol) in POCl₃ (15 mL) wasadded DIEA (2 mL) at 0° C., which was heated to 30° C. and stirred foro.n. The reaction was concentrated in vacuo. H₂O (15 mL) and MeOH (3 mL)were added at 0° C., which was stirred at r.t. for 1 h. The mixture wasfiltered and the filtrate cake was collected by filtration to giveExample 23c (1.5 g, 50.1% yield) as a yellow solid. LCMS [M+1]⁺=221.0

Step 3: Example 23e

To a solution of Example 23c (1.2 g, 5.42 mmol) and Example 23d (1.21 g.5.96 mmol) in EtOH (30 mL) was added conc. HCl (5 mL) and the solutionwas heated to reflux for o.n. The reaction was concentrated in vacuo.The residue was dissolved in EtOAc (100 mL) and H₂O (50 mL), and the pHwas adjusted to ˜8 with sat. NaHCO₃. The organic layer was separated andconcentrated. The residue was purified by silica gel chromatography(DCM/MeOH=30/1) to afford the product Example 23e (700 mg, 33.1% yield)as a yellow solid. LCMS [M+1]⁺=389.1

Step 4: Example 23f

To a solution of Example 23e (690 mg, 1.78 mmol) in THF (30 mL) and H₂O(10 mL) cooled at 0° C. was added LiOH.H₂O (112 mg, 2.67 mmol) and thesolution was stirred at r.t. for o.n. The reaction was concentrated invacuo. The residue was dissolved in H₂O (50 mL), adjusted pH ˜4 with HCl(2 mol/L), and extracted with EtOAc (100 mL). The organic layer wasconcentrated to afford the crude product Example 23f (750 mg, 100% crudeyield) as a yellow solid. LCMS [M+1]⁺=375.2

Step 5: Example 23g

To a solution of Example 23f (500 mg, 1.33 mmol) in DMF (10 mL) wereadded DIEA (515 mg, 3.99 mmol), HATU (610 mg, 1.60 mmol) and CD₃—NH₂.HCl(110 mg, 1.59 mmol) and the solution was stirred at r.t. for 2 h. Thereaction was diluted with EtOAc (50 mL), washed with brine (10 mL* 3),dried over Na₂SO₄, and concentrated in vacuo. The residue was purifiedby silica gel chromatography (DCM/MeOH=30/1) to afford the productExample 14g (510 mg, 98% yield) as a light yellow solid. LCMS[M+1]⁺=391.0

Step 6: Example 23h

To a mixture of Example 23g (500 mg, 1.278 mmol), Example 23h (33 mg,1.917 mmol) and Cs₂CO₃ (167 mg, 2.55 mmol) in dioxane (5 mL) was added3^(rd) t-Bu-Xphos-Pd (22.5 mg, 0.128 mmol). The mixture was degassedwith N₂ three times, then heated to 100° C. and stirred for overnight.The reaction was concentrated in vacuo. The residue was further purifiedby prep-HPLC to give the desired product Example 23h (60 mg, 54.2%yield) as a white solid. LCMS [M+1]⁺=440.1. ¹H NMR (300 MHz, DMSO-d₆) δ9.29 (s, 1H), 8.56 (s, 1H), 8.43 (s, 1H), 7.74 (d, J=6.8 Hz, 1H), 7.39(d, J=7.6 Hz, 1H), 7.29 (t, J=7.8 Hz, 1H), 3.94 (s, 3H), 3.70 (s, 3H),1.65-1.80 (m, 1H), 0.8-0.94 (m, 4H).

Step 7: Example 23

To a solution of Example 23h (50 mg, 0.11 mmol, 1.0 eq) in pyridine (2.0mL) was added pyridine hydrofluoride (70% in pyridine, 0.5 mL) followedby NaNO₂ (10 mg, 0.15 mmol, 1.4 eq) at 0° C. very slowly and theresulting mixture was stirred for 20 min. The reaction was concentratedin vacuo. The residue was purified by prep-HPLC to give the desiredproduct Example 23 (13.5 mg, 28.1% yield) as a light yellow solid. LCMS[M+1]⁺=443.3. ¹H NMR (300 MHz, DMSO-d₆) δ 10.87 (s, 1H), 10.29 (s, 1H),8.56 (s, 1H), 8.31 (s, 1H), 7.89 (s, 1H), 7.61 (dd, J=7.8 Hz, J=1.8 Hz,1H), 7.45 (d, J=8.0 Hz, 1H), 7.24 (d, J=7.8 Hz, 1H), 3.95 (s, 3H), 3.72(s, 3H), 1.95-1.91 (m, 1H), 0.79-0.77 (m, 4H).

Example 24

Step 1: Example 24c

To a solution of Example 24a (50.00 g, 287 mmol, 1.0 eq) and TEA (31.9g, 316 mmol, 1.1 eq) in CH₃CN (1 L) was added Example 24b (70.3 g, 293mmol, 1.02 eq) in portions at 0° C. After addition, it was stirred for 1h at room temperature. The solid was removed by filtration, rinsed withMTBE. The filtrate was concentrated and then diluted with MTBE. Theslurry was stirred for 30 min, filtered and the filtrate wasconcentrated to provide Example 24c (52.47 g, crude) as brown oil.

Step 2: Example 24d

Example 24c (52.47 g, 262 mmol, 1.0 eq) was dissolved in MTBE (600 mL)and PPh₃ (68.74 g, 262 mmol, 1.0 eq) was added. The reaction solutionwas stirred 16 h at room temperature and then concentrated in vacuo. Tothe residual sludge was added AcOH (500 mL) and H₂O (50 mL). The vesselwas equipped with a condenser and the mixture was heated to reflux for 6h, and then concentrated in vacuo. The crude product (115.0 g, crude)was used to next step without purification.

Step 3: Example 24e

To last step crude product Example 24d (115.0 g, 32% purity, 216 mmol,1.0 eq) dissolved in THF (150 mL)/MeOH (50 mL)/H₂O (50 mL) was addedLiOH.H₂O (36.3 g, 864 mmol, 4.0 eq) and the reaction mixture was stirredfor 16 at room temperature. After the reaction was completed, MeOH andTHF were concentrated. The residue was diluted with H₂O (200 mL), andthen extracted with EtOAc (300 mL*3). Then of the aqueous phase wasadjusted to 3 with conc. HCl. Acidification of the water solutionafforded a brown precipitate which was collected by filtration and driedin vacuo to afford Example 24e (31.5 g, 93.5% yield) as a yellow solid.

Step 4: Example 24f

The solution of Example 24e (15.0 g, 96.15 mmol, 1.0 eq) in POCl₃ (150mL) was stirred for 4 h at 100° C. After the reaction was completed, itwas concentrated in vacuo to give Example 24f (17.4 g, crude), which wasused to next step without further purification.

Step 5: Example 24h

To a solution of Example 24g (2.30 g, 23.70 mmol, 2.0 eq) and DIEA(12.23 g, 94.79 mmol, 8.0 eq) in THF (50 mL) was added the solution ofExample 24f (2.5 g, 11.85 mmol, 1.0 eq) in DCM (25 mL) dropwise at 0° C.The reaction solution was stirred for 30 min at r.t. The reactionsolution was diluted with EtOAc (100 mL), washed with brine (80 mL*3),dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residue waspurified by silica gel chromatography (Petroleum Ether/EtOAc=1/2) toafford the product Example 24h (1.8 g, 64.4% yield) as a yellow solid.LCMS [M+1]⁺=236.2

Step 6: Example 24j

To a solution of Example 24h (700 mg, 2.98 mmol, 1.0 eq) and Example 24i(611 mg, 2.98 mmol, 1.0 eq) in dry THF (15 mL) was add LiHMDS (5.96 mL,1M, 2.0 eq) dropwise at −30° C. under N₂. The reaction mixture wasstirred for 30 min at r.t. The crude product was concentrated andpurified by silica gel chromatography (DCM/MeOH=10/1) to afford theproduct Example 24j (450 mg, 37.5% yield) as a yellow solid. LCMS[M+1]⁺=404.2.

Step 7: Example 24l

To the solution of Example 24j (450 mg, 1.12 mmol, 1.0 eq) in dioxane (5mL) were added Cs₂CO₃ (728 mg, 2.23 mmol, 2.0 eq), Example 24k (285 mg,3.35 mmol, 3.0 eq) and 3^(rd) t-Bu-Xphos catalyst (99 mg, 0.11 mmol, 0.1eq) and the reaction mixture was stirred for 4 h at 110° C. under N₂.The reaction solution was concentrated and purified by silica gelchromatography (DCM/MeOH=10/1) to afford the product Example 24l (320mg, 63.5% yield) as a yellow solid. LCMS [M+1]⁺=453.2.

Step 5: Example 24

To a solution of Example 24h (120 mg, 0.27 mmol, 1.0 eq) in THF (3 mL)was added CH₃MgBr (0.27 mL, 3.0 M, 3.0 eq) dropwise at 0° C. under N₂.The reaction solution was stirred for 30 min at r.t. The reactionsolution was poured into saturated aqueous NH₄Cl (10 mL), and extractedwith DCM (10 mL*3). The combined organic layer was washed with brine (30mL), dried by Na₂SO₄ and concentrated. The crude product was purified byprep-HPLC to give the desired product Example 24 (8.8 mg, 8.0% yield) asan off white solid. LCMS [M+1]⁺=408.3. ¹H NMR (300 MHz, DMSO-d₆) δ 11.52(s, 1H), 10.57 (s, 1H), 8.58 (s, 1H), 8.12 (s, 1H), 7.72 (d, J=7.6 Hz,1H), 7.53 (d, J=7.2 Hz, 1H), 7.30 (t, J=7.8 Hz, 1H), 3.96 (s, 3H), 3.71(s, 3H), 2.81 (s, 3H), 1.09-1.03 (m, 1H), 0.86-0.83 (m, 4H).

Example 25

Step 1 Example 25

To the solution of Example 25a (50 mg, 0.11 mmol, 1.0 eq) in THF (1 mL)was added CH₃MgBr (0.55 mL, 1.0 M, 5.0 eq) dropwise at 0° C. under N₂.The reaction solution was stirred for 30 min at r.t. The reactionsolution was purified by prep-TLC (DCM/MeOH=12/1) to obtained crudeproduct (27 mg) and further purified by prep-HPLC (Prep-C18, 5 μMXBridge column, 19×150 mm, Waters; gradient elution of 40% MeCN in waterto 50% MeCN in water over a 7 min period, where both solvents contain0.1% formic acid) to give the desired product Example 25 (6.8 mg, 14.6%yield) as a yellow solid (FA salt). LCMS [M+1]⁺=422.3. ¹H NMR (300 MHz,DMSO-d₆) δ 10.55 (s, 1H), 8.58 (s, 1H), 8.48 (br, 2H), 8.10 (s, 1H),7.71 (dd, J=7.8, 1.6 Hz, 1H), 7.52 (dd, J=7.8, 1.6 Hz, 1H), 7.29 (t,J=7.8 Hz, 1H), 3.95 (s, 3H), 3.72 (s, 3H), 3.36 (q, J=7.2 Hz, 2H),2.11-2.04 (m, 1H), 1.17 (t, J=7.2 Hz, 3H), 0.85-0.81 (m, 4H).

Example 26

To a solution of Example 26a (135 mg, 0.3 mmol) in dry THF (10 mL) wasadded Example 26b (1.2 mL, 1M in THF, 1.2 mmol) dropwise at 0° C. undernitrogen. After addition (about 5 min), the reaction mixture was stirredfor 1 h at r.t. Then, the reaction was quenched with MeOH (1 mL) andconcentrated in vacuo. The residue was purified by prep-TLC(DCM/MeOH=20/1) to afford the product Example 26 (19.5 mg, 15% yield) asan off-white solid. LCMS [M+1]⁺=434.3/. ¹H NMR (400 MHz, DMSO-d₆) δ11.53 (s, 1H), 10.61 (s, 1H), 8.57 (s, 1H), 8.11 (s, 1H), 7.72 (dd,J=7.8 Hz, 1.6 Hz, 1H), 7.52 (dd, J=7.8 Hz, 1.8 Hz, 1H), 7.29 (t, J=7.8Hz, 1H), 3.95 (s, 3H), 3.72-3.69 (m, 4H), 2.11-2.05 (m, 1H), 1.24-1.16(m, 4H), 0.85-0.82 (m, 4H).

Example 27

Step 1: Example 027c

To a solution of Example 057a (5 g, 21.3 mmol) and Example 027b (2.28 g,23.4 mmol) in THF (20 mL) were added Et₃N (3.28 g, 31.9 mmol) and EDCI(6 g, 31.9 mmmol). The mixture was stirred at r.t. overnight. Thereaction mixture was washed by brine (60 mL), and extracted by DCM (60mL*3). The combined organic layer was dried over Na₂SO₄, concentratedunder reduced pressure, and dried to give Example 027c (4.4 g, 95%yield) as a yellow solid. LCMS [M+1]⁺=234.9/236.9

Step 2: Example 027e

To a solution of Example 027c (4.4 g, 18.7 mmol), Example 027d (CAS:1609394-10-6, 4.2 g, 20.6 mmol) in THF (20 mL) under N₂ was added LiHMDS(1 mol/L, 28 mL, 28.05 mmol) dropwise. The mixture was stirred at r.t.for 1 h. The reaction mixture was washed by brine (60 mL), extracted byDCM (60 mL*3). The combined organic layer was dried over Na₂SO₄,concentrated under reduced pressure, purified by flash C-18 column(H₂O/CH₃CN=3/1) to give Example 027e (2.4 g, 32% yield) as yellow oil.LCMS [M+1]⁺=403.1

Step 3: Example 027g

To a solution of Example 027e (500 mg, 1.24 mmol) in THF (10 mL) underN₂, was added Example 027f (1 mol/L, 10 mL, 12.4 mmol) in one potion.The mixture was stirred at r.t. for 1 h. The reaction mixture was washedby brine (40 mL), and extracted by EtOAc (40 mL*3). The combined organiclayer was dried over Na₂SO₄,l concentrated under reduced pressure to getcrude product (600 mg, crude) as a yellow solid, which was directly usedin next step without further purification. LCMS [M+1]⁺=384.

Step 4: Example 027

To a solution of Example 027g (100 mg, 0.26 mmol), Example 027h (33.3 mg0.92 mmol) in 1,4-dioxane (2 mL) were added Cs₂CO₃ (127.3 mg 0.392mmol), Pd₂(dba)₃ (23.9 mg 0.026 mmol), and Xant-phos (15.1 mg 0.026mmol). The mixture was degassed by Ar, heated to 90° C. and stirred overnight. The reaction mixture was diluted by DCM and filtrated. Thefiltrate was concentrated under reduced pressure to remove solvent,which was further purified by prep-HPLC to give Example 027 (17.5 mg,15% yield) as a white solid. LCMS [M+1]⁺=433.2. ¹H NMR (400 MHz,Chloroform-d) δ 11.25 (s, 1H), 8.84 (s, 1H), 8.11 (s, 1H), 8.09 (s, 1H),7.80 (d, J=8.0, 1.6 Hz, 1H), 7.55 (d, J=8.0, 1.6 Hz, 1H), 7.27-7.29 (m,1H), 4.00 (s, 3H), 3.76 (s, 3H), 2.54-2.60 (m, 1H), 1.67-1.56 (m, 1H),1.26-1.29 (m, 2H), 1.04-1.10 (m, 4H), 0.87-0.93 (m, 2H).

Example 28

Step 1: Example 028b

To a suspension of Example 028a (20 g, 96.6 mmol) in MeCN (100 mL) andH₂O (15 mL) was added LiBr (25.2 g, 289.8 mmol), DIPEA (35.4 g, 289.8mmol). The mixture was stirred at 25° C. for 16 h. The reaction mixturewas isolated by filtration. The crude solid was washed with MeCN (25mL), dried under vacuum at 45° C. to give Example 028b (17.8 g, 93%yield) as a light yellow solid.

Step 2: Example 028d

To a suspension of Example 028b (17.5 g, 88.2 mmol) and Example 028c(15.0 g, 73.5 mmol) in H₂O (90 mL) and 2-propanol (15 mL) was addedZn(OAc)₂ (13.4 g, 73.5 mmol). The mixture was stirred at 65° C. for 15h. The reaction mixture was cooled to room temperature and isolated byfiltration. The crude solid was washed with water (45 mL) and THF (45mL). The solid was dried under vacuum at 70° C. to give Example 028d(25.2 g, 61% yield) as a light yellow solid.

Step 3: Example 28b

To a suspension of Example 28d (2.0 g, 5.10 mmol), CD₃NH₂HCl (431 mg,6.12 mmol) and NMI (293 mg, 3.57 mmol) in NMP/ACN (20 mL/20 mL) wereadded HOBt (344 mg, 2.55 mmol) and EDCI (1.37 g, 7.13 mmol). The mixturewas stirred at r.t. for 16 h. After cooling to 0° C., the mixture wasaged for 2 h at 0° C. The product was isolated by filtration. The wetcake was washed with H₂O (20 mL), and then ACN (20 mL). The solid wascollected and dried under vacuum to give Example 28b (1.1 g, 57.3%yield) as a white solid. LCMS [M+1]⁺=377.0

Step 4: Example 28d

To a solution of Example 28b (1.1 g, 2.92 mmol) and Example 28c (512 mg,4.38 mmol) in 1,4-dioxane (15 mL) were added Pd₂(dba)₃ (267 mg, 0.29mmol), XantPhos (337 mg, 0.58 mmol) and Cs₂CO₃ (1.9 g, 5.84 mmol). Themixture was degassed by nitrogen for 3 times and stirred at 120° C. for4 h. The reaction was cooled to r.t. and concentrated. The residue waspurified by silica gel chromatography (DCM/MeOH=85/15) to give thedesired crude product Example 28d (1.08 g, 81.2% yield, ˜35% purity) asa yellow solid, which was used for the next step directly. LCMS[M+1]⁺=458.0

Step 5: Example 28e

To a solution of the crude Example 28d (1.08 g, 2.36 mmol) in DCM/MeOH(10 mL) was added 6N HCl/iPrOAc (20 mL). The mixture was stirred at r.t.for 16 h. The resulting mixture was concentrated, and the residue waspurified by silica gel chromatography (EtOAc/MeOH=85/15) to give thedesired product Example 28e (240 mg, 28.4% yield) as a yellow solid. CMS[M+1]⁺=358.0

Step 6: Example 28h

To a solution of Example 28g (200 mg, 3.51 mmol) and TEA (709 mg, 7.02mmol) in DCM (15 mL) was slowly added a solution of Example 28f (707 mg,3.51 mmol) in DCM (5 mL) at 0° C. The mixture was then stirred at r.t.for 1 h. The solvent was removed in vacuo, and the residue was purifiedby silica gel chromatography (Petroleum Ether/EtOAc=92/8) to give thedesired product Example 28h (470 mg, 60.4% yield) as a yellow solid.LCMS [M+1]⁺=223.0

Step 7: Example 28

To an ice-cooled solution of NaH (14.5 mg, 0.36 mmol, 60% w.t. % inmineral oil) in DMF (1 mL) under nitrogen atmosphere was added(dropwise) a solution of Example 28e (35.7 mg, 0.1 mmol) in DMF (1 mL).After 15 min, a solution of Example 28h (20.2 mg, 0.091 mmol) DMF (1 mL)was added. After 5 min, the cooling bath was removed and the reactionwas warmed to 80° C. and stirred for 2 h. The mixture was quenched byadding water, purified by prep-HPLC to give the desired product Example28 (1.1 mg, 2.8% yield) as a yellow solid. LCMS [M+1]⁺=441.0. ¹H NMR(400 MHz, DMSO-d₆) δ 10.89 (s, 1H), 9.60 (s, 1H), 9.00 (s, 1H), 8.54 (s,1H), 8.00 (s, 1H), 7.61 (dd, J=7.8, 1.6 Hz, 1H), 7.49 (dd, J=8.0, 1.6Hz, 1H), 7.24 (t, J=7.8 Hz, 1H), 3.99 (t, J=6.4 Hz, 4H), 3.93 (s, 3H),3.71 (s, 3H), 2.13 (p, J=7.6 Hz, 2H).

Example 29

Step 1: Example 29c

To a solution of Example 29b (1.0 g, 7.30 mmol) in 1,4-dioxane (15 mL)was treated with Example 29a (2 mL, 24.1 mmol) and stirred at r.t. for16 h. After the reaction was completed, the solvent was concentrated,and the residue was suspended in DCM (5 mL) and sonicated. The resultingsolid was collected via filtration, and dried to afford the desiredproduct Example 29c (665 mg, 80% yield) as a white solid. LCMS[M+1]⁺=115.0. ¹H NMR (400 MHz, DMSO-d₆) δ 5.62 (s, 2H), 3.18-3.12 (m,4H), 1.80-1.68 (m, 4H).

Step 2: Example 29

To a solution of Example 29d (50 mg, 0.13 mmol) and Example 29c (22.7mg, 0.20 mmol) in 1,4-dioxane (1 mL) were added Pd₂(dba)₃ (12.1 mg,0.013 mmol), XantPhos (15.3 mg, 0.026 mmol) and Cs₂CO₃ (86.5 mg, 0.27mmol). The mixture was sealed, degassed by nitrogen for 3 times andstirred at 110° C. for 2 h. When completed, the reaction was cooled tor.t. and filtered. The filtrate was purified directly by prep-HPLC togive the desired product Example 29 (13 mg, 21.7% yield) as a whitesolid. LCMS [M+1]⁺=455.0. ¹H NMR (400 MHz, DMSO-d₆) δ 10.88 (s, 1H),9.21 (s, 1H), 8.99 (s, 1H), 8.54 (s, 1H), 7.96 (s, 1H), 7.62 (dd, J=7.8,1.6 Hz, 1H), 7.49 (dd, J=8.0, 1.6 Hz, 1H), 7.25 (t, J=8.0 Hz, 1H), 3.93(s, 3H), 3.71 (s, 3H), 3.42-3.37 (m, 4h), 1.81 (s, 4H).

Example 30

Step 1: Example 30b

To a suspension of Example 30a (1.0 g, 2.55 mmol), CH₃NH₂HCl (206 mg,3.06 mmol) and NMI (146 mg, 1.78 mmol) in NMP/ACN (7 mL/7 mL) were addedHOBt (172 mg, 1.27 mmol) and EDCI (685 mg, 3.57 mmol). The mixture wasstirred at r.t. for 16 h. After cooling to 0° C., the mixture was agedfor 2 h at 0° C. The product was isolated by filtration. The wet cakewas washed with H₂O (10 mL), and then ACN (10 mL). The solid wascollected and dried under vacuum to give Example 30b (417 mg, 43.9%yield) as a white solid. LCMS [M+1]⁺=374.0

Step 2: Example 30

To a solution of Example 68b (72 mg, 0.19 mmol) and Example 30c (23 mg,0.23 mmol) in 1,4-dioxane (2 mL) were added Pd₂(dba)₃ (17.6 mg, 0.019mmol), XantPhos (22.3 mg, 0.038 mmol) and Cs₂CO₃ (125.5 mg, 0.38 mmol).The mixture was degassed by nitrogen for 3 times and stirred at 110° C.for 3.5 h in a sealed tube. When completed, the reaction was cooled tor.t. and filtered. The filtrate was purified directly by prep-HPLC togive the desired product Example 30 (16 mg, 19.0% yield) as a whitesolid. LCMS [M+1]⁺=438.0. ¹H NMR (400 MHz, DMSO-d₆) δ 10.88 (s, 1H),9.59 (s, 1H), 9.02 (d, J=5.4 Hz, 1H), 8.54 (s, 1H), 7.99 (s, 1H), 7.61(d, J=7.8 Hz, 1H), 7.49 (d, J=8.0 Hz, 1H), 7.24 (t, J=8.0 Hz, 1H), 3.98(s, 4H), 3.93 (s, 3H), 3.71 (s, 3H), 2.84 (d, J=4.4 Hz, 3H), 2.13 (t,J=7.8 Hz, 2H).

Example 31

Step 1: Example 31b

A solution of Example 31a (2.0 g, 5.4 mmol), TsNH₂ (1.1 g, 6.52 mmol),K₂CO₃ (1.1 g, 6.52 mmol) MeOH (5 mL) was stirred at r.t. for 10 min, andthen Example 31b (1.86 g, 13.6 mmol) in dry DMSO (20 mL) was added,which was stirred at 110° C. for o.n. When completed, the reaction wascooled to r.t., diluted by EtOAc, washed by water, and dried overNa₂SO₄. The organic layer was concentrated and purified by silica gelcolumn (Petroleum ether/EtOAc=4/1) to give Example 031b (600 mg, 52.1%yield) as a white solid. LCMS [M+1]⁺=214.1. ¹H NMR (400 MHz,Chloroform-d) δ 7.73 (d, J=7.8 Hz, 1H), 7.37 (d, J=7.8 Hz, 1H), 3.93 (d,J=6.6 Hz, 4H), 3.76 (d, J=7.4 Hz, 2H), 2.46 (s, 3H).

Step 2: Example 31c

A solution of Mg (676 mg, 28 mmol) in MeOH (5 mL) was stirred at r.t.for 10 min, then Example 31b (600 mg, 2.8 mmol) in MeOH (5 mL) wasadded, and the mixture reaction was stirred at r.t. for o.n. in a sealedtube. Another Mg (676 mg, 28 mmol) was added, and the mixture reactionwas stirred at r.t. for another 6 h. The mixture was filtered, and thesolid was washed by MeOH. The filtrate Example 31c was used directly fornext step. LCMS [M+1]⁺=61.2

Step 3: Example 31d

To a solution of Example 31c (crude in MeOH) was added (Boc)₂O (940 mg,5.6 mmol), which was stirred at r.t. for o.n. The mixture was filtered,and the solid was washed by MeOH. The organic layer was added additional(Boc)₂O (940 mg, 5.6 mmol), which was stirred at r.t. for another 4 h.After reaction was completed, the mixture was concentrated and purifiedby silica gel column (Petroleum Ether/EtOAc=5/1) to give Example 031d(500 mg, crude, containing (Boc)₂O) as a white solid. LCMS[M+1−56]⁺=104.1. ¹H NMR (400 MHz, Chloroform-d) 3.93 (d, J=6.6 Hz, 4H),1.43 (s, 9H).

Step 4: Example 31c

A solution of Example 31d (500 mg, 3.1 mmol) in con. HCl (1 mL) wasstirred at r.t for 0.5 h. After reaction was completed, the mixture wasconcentrated to give Example 31c (200 mg, 67.9% yield) as a white solid,which was used for next step without further purification. LCMS[M+1]⁺=60.2.

Step 5: Example 31f

To a solution of Example 31c (200 mg, 3.3 mmol) and DIEA (3.3 g, 33mmol) in 1,4-dioxane (5 mL) was added Example 31e (230 mg, 1.67 mmol),which was stirred at r.t. for o.n. After reaction was completed, themixture was concentrated, and directly purified by silica gel column(DCM/MeOH=10/1) to give the desired product Example 31f (230 mg, crude,containing DIEA, 67.6% yield) as colorless oil. LCMS [M]⁺=103.2

Step 6: Example 31

To a solution of Example 31f (200 mg, ˜50% purity, 0.5 mmol) and Example31g (188 mg, 0.5 mmol) in 1,4-dioxane (5 mL) were added Pd₂(dba)₃ (45mg, 0.05 mmol), XantPhos (30 mg, 0.05 mmol) and Cs₂CO₃ (489 mg, 1.5mmol). The mixture was degassed by nitrogen for 3 times, sealed, andstirred at 110° C. for 2 h. When completed, the reaction was cooled tor.t. and filtered. The filtrate was purified directly by prep-HPLC togive the desired product Example 31 (2.2 mg, 1% yield) as a white solid.LCMS [M+1]⁺=442.2. ¹H NMR (400 MHz, DMSO-₆) δ 10.90 (s, 1H), 9.60 (s,1H), 9.00 (s, 1H), 8.54 (s, 1H), 8.00 (s, 1H), 7.61 (d, J=7.8 Hz, 1H),7.49 (d, J=8.0 Hz, 1H), 7.24 (t, J=8.0 Hz, 1H), 3.97 (s, 4H), 3.93 (s,3H), 3.71 (s, 3H).

Example 32

Step 1: Example 32c

To a solution of Example 32a (300 mg, 2.19 mmol) in 1,4-dioxane (5 mL)were treated with Example 32b (623 mg, 3.28 mmol) and TEA (664 mg, 6.57mmol). The mixture was stirred at r.t. for 16 h. After completion, themixture was concentrated, and the residue was suspended in DCM (5 mL)and sonicated. The resulting solid was collected via filtration, anddried to afford the desired product Example 32c (226 mg, 73.9% yield) asa white solid.

LCMS [M+1]⁺=141.0

Step 2: Example 32

To a solution of Example 32d (60 mg, 0.16 mmol) and Example 32c (26.7mg, 0.19 mmol) in 1,4-dioxane (0.6 mL) were added Pd₂(dba)₃ (14.6 mg,0.016 mmol), XantPhos (18.4 mg, 0.032 mmol) and Cs₂CO₃ (104 mg, 0.32mmol). The mixture was degassed by nitrogen for 3 times and stirred at110° C. for 16 h in a sealed tube. When completed, the reaction wascooled to r.t. and filtered. The filtrate was purified directly byprep-HPLC to give the desired product Example 32 (6.6 mg, 8.7% yield) asa white solid. LCMS [M+1]⁺=481.0. ¹H NMR (400 MHz, DMSO-d₆) δ 10.87 (s,1H), 9.61 (s, 1H), 8.99 (s, 1H), 8.55 (s, 1H), 7.97 (s, 1H), 7.61 (d,J=7.8 Hz, 1H), 7.48 (d, J=8.0 Hz, 1H), 7.24 (t, J=8.0 Hz, 1H), 3.93 (s,7H), 3.69 (s, 3H), 2.08 (t, J=7.5 Hz, 4H), 1.80-1.67 (m, 2H).

Example 33

Step 1: Example 33c

To a solution of Example 33a (500 mg, 3.65 mmol, 1.0 eq) in dioxane (6ml) was added Example 33b (624 mg, 10.95 mmol, 3.0 eq). The reactionsolution was stirred for 16 h at r.t. and concentrated. The residue wastreated with DCM. The resulting solid was collected by filtration toafford Example 33c (190 mg, 52% yield) as a white solid. ¹H NMR (300MHz, DMSO-d₆) δ 5.72 (brs, 2H), 3.76 (t, J=7.6 Hz, 4H), 2.14-2.04 (m,2H).

Step 2: Example 33

To a solution of Example 33d (100 mg, 0.26 mmol, 1.0 eq) and Example 33c(78.0 mg, 0.78 mmol, 3.0 eq) in dioxane (4 mL) were added Xantphos (30.1mg, 0.05 mmol, 0.2 eq), Cs₂CO₃ (169.5 mg, 0.52 mmol, 2.0 eq) andPd₂(dba)₃.CHCl₃ (26.9 mg, 0.03 mmol, 0.1 eq). The reaction mixture wasstirred at 110° C. for 4 h under N₂ protection. The solid was filteredout and filtrate was concentrated, and the residue was purified byprep-TLC (DCM/MeOH=15/1) to afford the Example 33 (43.3 mg, 37% yield)as an off-white solid. LCMS [M+1]⁺=448.2. ¹H NMR (300 MHz, DMSO-d₆) δ11.00 (s, 1H), 9.20 (s, 1H), 9.05 (s, 1H), 8.56 (s, 1H), 7.91 (s, 1H),7.62 (dd, J=7.8, 1.6 Hz, 1H), 7.53 (dd, J=8.0, 1.6 Hz, 1H), 7.25 (t,J=7.8 Hz, 1H), 4.00-3.70 (m, 7H), 3.70 (s, 3H), 3.01-2.91 (m, 1H),2.19-2.09 (m, 2H), 1.12-0.99 (m, 4H).

Example 34

Step 1: Example 34b

To a solution of Example 34a (10.0 g, 42.7 mmol, 1.0 eq) in DCM (100 mL)was added BBr₃ (11.8 g, 46.9 mmol, 1.1 eq) dropwise at 0° C. The mixturewas stirred for 2 h at r.t. The mixture was quenched with MeOH (12 mL),washed with brine (50 mL*3), dried over Na₂SO₄, and concentrated toafford the product Example 34b (9.2 g, 98% yield) as an orange solid.LCMS [M+1]⁺=221.2.

Step 2: Example 34c

To a solution of Example 34b (9.2 g, 41.8 mmol, 1.0 eq) in ACN (184 mL)were added K₂CO₃ (11.6 g, 83.6 mmol, 2.0 eq) and CD₃I (7.3 g, 50.2 mmol,1.2 eq). The reaction mixture was stirred for 6 h at 80° C. After thereaction was completed, the reaction mixture was concentrated andpurified by silica gel chromatography (Petroleum Ether/EtOAc=2/1) toafford the product Example 34c (3.9 g, 39% yield) as an orange solid.LCMS [M+1]⁺=238.2.

Step 3: Example 34d

To a solution of Example 34c (3.9 g, 16.4 mmol, 1.0 eq) in MeOH (78 mL)was added Pd/C (780 mg) under N₂ protection. The suspension was degassedunder vacuum and purged with H₂ three times. The reaction mixture wasstirred at r.t. for 48 h under H₂ balloon. The solid was filtered out,and the filtrate was concentrated. The residue was purified by silicagel chromatography (Petroleum Ether/EtOAc=1/1) to afford the productExample 34d (1.9 g, 56% yield) as an off-white solid. LCMS [M+1]⁺=208.2.

Step 4: Example 34f

To a solution of Example 34e (450 mg, 1.91 mmol 1.0 eq) and Example 34d(396 mg, 1.91 mmol, 1.0 eq) in dry THF (15 mL) was added LiHMDS (3.8 mL,1 M in THF, 2.0 eq) dropwise at −20° C. under N₂ protection. Thereaction mixture was stirred for 0.5 h at r.t., and then the silica wasadded to the mixture and concentrated. The residue was purified bysilica gel chromatography (DCM/MeOH=20/1) to afford the product Example34f (450 mg, 58% yield) as a yellow solid. LCMS [M+1]⁺=406.2.

Step 5: Example 34h

To a solution of Example 34f (200 mg, 0.49 mmol, 1.0 eq) in THF (4 mL)was added Example 34g (3.0 mL, 1.0 M in THF, 6.0 eq) dropwise at 0° C.under N₂ protection. The mixture was stirred for 0.5 h at r.t. Thereaction was poured into saturated aqueous NH₄Cl (10 mL) and extractedwith EtOAc (15 mL*3). The combined organic layer was washed with brine,dried over Na₂SO₄, and concentrated. The crude product was purified bysilica gel chromatography (DCM/MeOH=20/1) to afford the product Example34h (160 mg, 84% yield) as a yellow solid. LCMS [M+1]⁺=387.1.

Step 6: Example 34

To a solution of Example 34h (100 mg, 0.26mmol, 1.0 eq) in dioxane (4mL) were added Cs₂CO₃ (169 mg, 0.52 mmol, 2.0 eq), Example 34l (66 mg,0.77 mmol, 3.0 eq), Xantphos (30 mg, 0.05 mmol, 0.2 eq) andPd₂(dba)₃.CHCl₃ (27 mg, 0.03 mmol, 0.1 eq). The reaction mixture wasstirred for 4 h at 110° C. under N₂ protection. After cooled to roomtemperature, the solvent was removed, and the crude product was purifiedby prep-TLC (DCM/MeOH=15/1) to afford the product Example 34 (30.9 mg,27% yield) as a yellow solid. LCMS [M+1]⁺=436.2. ¹H NMR (300 MHz,DMSO-d₆) δ 11.01 (s, 1H), 10.93 (s, 1H), 9.13 (s, 1H), 8.56 (s, 1H),8.04 (s, 1H), 7.64 (d, J=7.6 Hz, 1H), 7.52 (d, J=7.8 Hz, 1H), 7.26 (t,J=7.8 Hz, 1H), 3.95 (s, 3H), 3.05-2.90 (m, 1H), 2.05-2.00 (m, 1H),1.14-1.03 (m, 4H), 0.81 (d, J=6.4 Hz, 4H).

Example 35

Step 1: Example 35c

To a solution of Example 35a (10.0 g, 94.79 mmol, 1.0 eq) in CH₃CN (50mL) was added propan-2-amine (5.59 g, 94.79 mmol, 1.0 eq) at 0° C. Thereaction solution was stirred for 2 h at room temperature. The resultingsolid was collected by filtration to afford Example 35b (8.07 g) as awhite solid. The solid was dissolved in THF (150 mL), followed by NaH(5.83 g, 60% in mineral oil, 145.8 mmol, 3.0 eq) in portions at 0° C.The mixture was stirred for 16 h at room temperature. The reaction wasquenched with H₂O and extracted with EtOAc. The combined organic layerwas washed with brine, dried by Na₂SO₄ and concentrated. The crudeproduct was purified by silica gel chromatography (DCM/MeOH=30/1) togive the desired product Example 35c (3.50 g, 29% yield) as a whitesolid. ¹H NMR (300 MHz, CDCl₃-d) δ 5.07 (s, 1H), 4.21-4.06 (m, 1H), 3.38(s, 4H), 1.13 (d, J=6.6 Hz, 6H).

Step 2: Example 35f

To a solution of Example 35d (10.0 g, 52.08 mmol, 1.0 eq) in DCM (200mL) were added DIEA (33.59 g, 260.4 mmol, 5.0 eq) and HATU (23.75 g,62.50 mmol, 1.2 eq). After stirred for 30 min, Example 35e (6.09 g,62.50 mmol, 1.2 eq) was added to the solution. The reaction solution wasstirred for 1 h at room temperature. After the reaction was completed,the solvent was removed and the crude was purified by silica gelchromatography (Petroleum Ether/EtOAc=3/1) to give the desired productExample 35f (11.5 g, 94.0% yield) as a yellow solid. LCMS [M+1]⁺=235.0.

Step 3: Example 35h

To a solution of Example 35f (5.0 g, 21.28 mmol, 1.0 eq) and Example 35g(4.36 g, 21.28 mmol, 1.0 eq) in THF (100 mL) was added LiHMDS (42.55 mL,1 M in THF, 2.0 eq) dropwise at −15° C. under N₂. The reaction solutionwas stirred for 1 h at r.t. And then the silica was added to the mixtureand concentrated. The residue was purified by silica gel chromatography(DCM/MeOH=50/1) to give the desired product Example 35h (4.02 g, 46.9%yield) as a yellow solid. LCMS [M+1]⁺=403.2.

Step 4: Example 35j

To a solution of Example 35h (2.0 g, 4.98 mmol, 1.0 eq) in THF (100 mL)was added Example 35i (39.80 mL, 39.80 mmol, 1 M, 8.0 eq) dropwise at−10° C. under N₂. The reaction solution was stirred for 1 h at r.t. Thereaction solution was quenched with saturated aqueous NH₄Cl andextracted with EtOAc. The combined organic layer was washed with brine,dried by Na₂SO₄ and concentrated. The crude product was purified bysilica gel chromatography (DCM/MeOH=20/1) to give the desired productExample 35j (1.90 g, 99.7% yield) as a yellow solid. LCMS [M+1]⁺=384.2.

Step 5: Example 35

To the solution of Example 35j (100 mg, 0.26 mmol, 1.0 eq) in dioxane (3mL) were added Example 70c (100 mg, 0.78 mmol, 3.0 eq), Cs₂CO₃ (170 mg,0.52 mmol, 2.0 eq), Xantphos (15 mg, 0.026 mmol, 0.1 eq) andPd₂(dba)₃CHCl₃ (27 mg, 0.026 mmol, 0.1 eq). The reaction solution wasstirred for 4 h at 110° C. under N₂. The reaction solution was filteredand the filtrate was concentrated. The crude product was purified byPrep-TLC (DCM/MeOH=15/1) to give the desired product Example 35 (31.3mg, 25.3% yield) as an off white solid. LCMS [M+1]⁺=476.3. ¹H NMR (300MHz, DMSO-d₆) δ 10.93 (s, 1H), 9.14 (s, 1H), 8.56 (s, 1H), 8.17 (s, 1H),7.62 (dd, J=7.8, 1.8 Hz, 1H), 7.56 (dd, J=8.4 Hz, 1.6 Hz, 1H), 7.26 (t,J=7.8 Hz, 1H), 4.12-3.99 (m, 3H), 3.95 (s, 3H), 3.70 (s, 3H), 3.41 (t,J=8.0 Hz, 2H), 3.04-2.91 (m, 1H), 1.17-1.06 (m, 8H), 1.06-0.98 (m, 2H).

Example 36

To a solution of Example 36a (70 mg, 0.18 mmol, 1.0 eq)) in dioxane (2mL) were added Example 36b (48 mg, 0.55 mmol, 3.0 eq), Cs₂CO₃ (11.9 mg,0.37 mmol, 2.0 eq), Xantphos (11 mg, 0.018 mmol, 0.1 eq) andPd₂(dba)₃.CHCl₃ (19 mg, 0.018 mmol, 0.1 eq). The reaction solution wasstirred for 4 h at 110° C. under N₂. The reaction solution was filteredand the filtrate was concentrated. The crude product was purified byprep-TLC (DCM/MeOH=15/1) to give the desired product Example 36 (30.9mg, 39.0% yield) as an off-white solid.

LCMS [M+1]⁺=435.2. ¹H NMR (300 MHz, DMSO-d₆) δ 11.02 (s, 1H), 10.56 (s,1H), 9.12 (s, 1H), 8.56 (s, 1H), 8.08 (s, 1H), 7.66 (dd, J=7.8, 1.5 Hz,1H), 7.56 (dd, J=7.8, 1.5 Hz, 1H), 7.29 (t, J=7.4 Hz, 1H), 3.95 (s, 3H),3.70 (s, 3H), 3.06-2.94 (m, 1H), 2.83-2.69 (m, 1H), 1.15-1.08 (m, 2H),1.08-0.98 (m, 8H).

Example 37

To a solution of Example 37a (100 mg, 0.26 mmol, 1.0 eq) in dioxane (3mL) were added Example 37b (49 mg, 0.52 mmol, 3.0 eq), Cs₂CO₃ (170 mg,0.52 mmol, 2.0 eq), and 3^(rd) t-Bu-Xphos Pd (23 mg, 0.026 mmol, 0.1eq). The reaction solution was stirred for 6 h at 110° C. under N₂. Thereaction solution was filtered and the filtrate was concentrated. Thecrude product was purified by Prep-TLC (DCM/MeOH=15/1) to give thedesired product Example 37 (21.0 mg, 18.3% yield) as a light yellowsolid. LCMS [M+1]⁺=442.2. ¹H NMR (300 MHz, DMSO-d₆) δ 11.08 (s, 1H),9.98 (s, 1H), 9.10 (s, 1H), 8.56 (s, 1H), 8.19 (d, J=4.8 Hz, 1H), 8.01(s, 1H), 7.69 (t, J=8.0 Hz, 2H), 7.60 (t, J=8.0 Hz, 2H), 7.31 (t, J=8.0Hz, 1H), 6.96-6.88 (m, 1H), 3.96 (s, 3H), 3.72 (s, 3H), 3.04-2.91 (m,1H), 1.14-0.94 (m, 4H).

Example 38

Step 1: Example 38c

A solution of Example 38b (1.13 g, 8.2 mmol) in 1,4-dioxane (10 mL) weretreated with Example 38a (1.0 g, 8.2 mmol) and TEA (2.5 g, 24.7 mmol).The mixture was stirred at r.t. for 16 h. After the reaction wascompleted, the solution was concentrated, and the residue was suspendedin a mixed solution (Petroleum Ether/EtOAc=1/1, 10 mL), and sonicated.The resulting solid was collected via filtration, dried to afford thedesired product Example 38c (1.0 g, 94.3% yield) as a white solid, whichcontained some TEA.HCl LCMS [M+1]⁺=129.0

Step 2: Example 38

To a solution of Example 38d (250 mg, 0.66 mmol) and Example 38c (127mg, 0.99 mmol) in 1,4-dioxane (4 mL) were added Pd₂(dba)₃ (60 mg, 0.068mmol), Xantphos (77.5 mg, 0.13 mmol) and Cs₂CO₃ (433 mg, 1.32 mmol). Themixture was sealed, degassed by nitrogen for 3 times and stirred at 110°C. for 16 h. When completed, the reaction was cooled to r.t. andfiltered. The filtrate was purified directly by prep-HPLC to give thedesired product Example 38 (116 mg, 37.4% yield) as a yellow solid. LCMS[M+1]⁺=469.0. ¹H NMR (400 MHz, DMSO-d₆) δ 10.91 (s, 1H), 9.58 (s, 1H),8.99 (s, 1H), 8.54 (s, 1H), 8.02 (s, 1H), 7.62 (d, J=7.7 Hz, 1H), 7.49(d, J=7.8 Hz, 1H), 7.24 (t, J=7.9 Hz, 1H), 3.93 (s, 3H), 3.72 (s, 3H),3.66 (s, 4H), 1.17 (s, 6H).

Examples 89-104 were synthesized as described for examples 1-88.

Example 105

To a solution of Example 105a (100 mg, 0.26 mmol, 1.0 eq), Example 105b(57.0 mg, 0.78 mmol, 3.0 eq) in dioxane (3 mL) were added Cs₂CO₃ (169.5mg, 0.52 mmol, 2.0 eq) and 3^(rd)-t-Bu-xphos-Pd (26.7 mg, 0.03 mmol, 0.1eq). The reaction mixture was stirred at 110° C. for 4 h under N₂protection. The solid was filtered out and filtrate was concentrated.The residue was purified by Prep-TLC (DCM/MeOH=15/1) to afford Example105 (36.1 mg, 33% yield) as a yellow solid. LCMS [M+1]⁺=421.3. ¹H NMR(300 MHz, DMSO-d₆) δ 11.02 (s, 1H), 10.56 (s, 1H), 9.12 (s, 1H), 8.57(s, 1H), 8.07 (s, 1H), 7.66 (dd, J=7.8, 1.5 Hz, 1H), 7.55 (dd, J=7.8,1.5 Hz, 1H), 7.28 (t, J=7.8 Hz, 1H), 3.95 (s, 3H), 3.70 (s, 3H),3.06-2.93 (m, 1H), 2.39 (q, J=7.5 Hz, 2H), 1.16-0.96 (m, 7H).

Example 106

To a solution of Example 106a (50 mg, 0.13 mmol, 1.0 eq,) and Example106b (13.9 mg, 0.20 mmol, 1.5 eq) in dioxane (3 mL) were added Cs₂CO₃(84.9 mg, 0.26 mmol, 2.0 eq), Pd₂(dba)₃.CHCl₃ (13.5 mg, 0.013 mmol, 0.1eq) and Xantphos (15.1 mg, 0.026 mmol, 0.2 eq). The reaction mixture wasstirred for 2 h at 110° C. under N₂ protection. The mixture was filteredand the filtrate was concentrated in vacuo. The crude product waspurified by pre-HPLC (DCM/MeOH=25/1) to afford the desired productExample 106 (5.9 mg, 10.8% yield) as a white solid. LCMS [M+1]⁺=419.3.¹H NMR (300 MHz, DMSO-d₆) δ 11.04 (s, 1H), 10.86 (s, 1H), 9.15 (s, 1H),8.57 (s, 1H), 8.17 (s, 1H), 7.67 (dd, J=7.8, 1.5 Hz, 1H), 7.59-7.56(m,1H), 7.29 (t, J=7.8 Hz, 1H), 6.61 (dd, J=16.8, 10.2 Hz, 1H), 6.28 (dd,J=16.8, 1.8 Hz, 1H), 5.81 (d, J=11.7 Hz, 1H), 3.96 (s, 3H), 3.71 (s,3H), 3.05-2.95 (m, 1H), 1.15-0.95 (m, 4H).

Example 107

To a solution of Example 107a (110 mg, 0.29 mmol) and Example 107b (93mg, 0.86 mmol) in 1,4-dioxane (2 mL) were added Pd₂(dba)₃ (26 mg, 0.029mmol), Xantphos (33 mg, 0.057 mmol) and Cs₂CO₃ (187 mg, 0.57 mmol). Themixture was degassed by nitrogen for 3 times and stirred at 110° C. for1 h. When completed, the reaction was cooled to r.t., diluted with MeOH(5 mL) and filtered. The filtrate was purified directly by Prep-HPLC togive the desired product Example 107 (24 mg, 18.5% yield) as a yellowsolid. LCMS [M+1]⁺=456.0. ¹H NMR (400 MHz, DMSO-d₆) δ 11.04 (s, 1H),9.88 (s, 1H), 9.07 (s, 1H), 8.55 (s, 1H), 8.03 (d, J=5.1 Hz, 1H), 7.97(s, 1H), 7.66 (d, J=8.1 Hz, 1H), 7.57 (d, J=7.8 Hz, 1H), 7.39 (s, 1H),7.27 (t, J=8.0 Hz, 1H), 6.74 (d, J=4.9 Hz, 1H), 3.93 (s, 3H), 3.69 (s,3H), 2.94 (s, 1H), 2.24 (s, 3H), 1.05 (s, 2H), 0.99 (d, J=7.6 Hz, 2H).

Example 108

To a solution of Example 108a (100 mg, 0.26 mmol) and Example 108b (44mg, 0.39 mmol) in 1,4-dioxane (2 mL) were added Pd₂(dba)₃ (24 mg, 0.026mmol), Xantphos (30 mg, 0.052 mmol) and Cs₂CO₃ (170 mg, 0.52 mmol). Themixture was degassed by nitrogen for 3 times and stirred at 110° C. for2 h. When completed, the reaction was cooled to r.t., diluted with MeOH(5 mL) and filtered. The filtrate was purified directly by Prep-HPLC togive the desired product Example 108 (18 mg, 15.1% yield) as a whitesolid. LCMS [M+1]⁺=460.0. ¹H NMR (400 MHz, DMSO-d₆) δ 11.01 (s, 1H),10.15 (s, 1H), 9.11 (s, 1H), 8.54 (s, 1H), 8.20 (t, J=7.5 Hz, 1H), 7.69(s, 1H), 7.63 (q, J=8.2, 5.8 Hz, 3H), 7.28 (t, J=8.0 Hz, 1H), 6.83 (s,1H), 3.93 (s, 3H), 3.69 (s, 3H), 2.95 (s, 1H), 1.07 (s, 2H), 1.00 (d,J=7.4 Hz, 2H).

Example 109

To a solution of Example 109a (100 mg, 0.26 mmol) and Example 109b (30mg, 0.31 mmol) in DMA (2.5 mL) were added Pd₂(dba)₃ (24 mg, 0.026 mmol),xantphos (30 mg, 0.052 mmol) and Cs₂CO₃ (340 mg, 1.04 mmol). The mixturewas degassed by nitrogen for 3 times and stirred at 130° C. for 2 h.When completed, the reaction was cooled to r.t., diluted with MeOH (5mL) and filtered. The filtrate was purified directly by Prep-HPLC togive the desired product Example 109 (25 mg, 21.7% yield) as a whitesolid. LCMS [M+1]⁺=443.0. ¹H NMR (400 MHz, DMSO-d₆) δ 11.04 (s, 1H),10.34 (s, 1H), 9.10 (s, 1H), 8.77 (d, J=4.4 Hz, 1H), 8.56 (s, 1H), 8.07(d, J=9.1 Hz, 1H), 7.72 (s, 1H), 7.62 (dd, J=12.0, 8.1 Hz, 2H), 7.55(dd, J=9.2, 4.5 Hz, 1H), 7.24 (t, J=7.9 Hz, 1H), 3.93 (s, 3H), 3.70 (s,3H), 2.95 (t, J=7.4 Hz, 1H), 1.06 (d, J=4.1 Hz, 2H), 1.00 (d, J=7.4 Hz,2H).

Example 110

Step 1: Example 110c

To a stirred solution of Example 110a (1.0 g, 5.78 mmol), xphos (551 mg,1.16 mmol), Pd₂(dba)₃ (530 mg, 0.58 mmol) and Example 110b (2.5 g, 28.9mmol) in THF (12 mL) was added LiHMDS (32 mL, 1.0 M in THF) and theresulting reaction was heated to 65° C. and stirring continued for 2 h.The reaction was poured into water (100 mL) and extracted with EtOAc(150 mL*2) and DCM (150 mL*2). The combined organic layers were driedover Na₂SO₄, filtered and concentrated to give a residue which waspurified by flash chromatography on a 40 g silica gel column(PE/EtOAc=0/100) to give the desired product Example 110c (900 mg, 87.4%yield) as a brown solid. LCMS [M+1]⁺=180.0

Step 2: Example 110

To a solution of Example 110c (70 mg, 0.39 mmol) and Example 110d (100mg, 0.26 mmol) in 1,4-dioxane (2 mL) were added Pd₂(dba)₃ (24 mg, 0.026mmol), xantphos (30 mg, 0.052 mmol) and Cs₂CO₃ (170 mg, 0.52 mmol). Themixture was degassed by nitrogen for 3 times and stirred at 110° C. for2 h. When completed, the reaction was cooled to r.t., diluted with MeOH(5 mL) and filtered. The filtrate was purified directly by Prep-HPLC togive the desired product Example 110 (22 mg, 16.1% yield) as a yellowsolid. LCMS [M+1]⁺=527.0. ¹H NMR (400 MHz, DMSO-d₆) δ 11.06 (s, 1H),9.74 (s, 1H), 9.04 (s, 1H), 8.54 (s, 1H), 7.85 (d, J=3.0 Hz, 1H), 7.79(s, 1H), 7.65 (d, J=8.1 Hz, 1H), 7.57 (d, J=7.9 Hz, 1H), 7.50 (d, J=19.1Hz, 1H), 7.39 (dd, J=9.1, 3.0 Hz, 1H), 7.29 (t, J=8.0 Hz, 1H), 3.93 (s,3H), 3.72 (t, J=4.5 Hz, 4H), 3.69 (s, 3H), 3.04 (t, J=4.7 Hz, 4H), 2.92(s, 1H), 1.04 (d, J=4.9 Hz, 2H), 0.97 (d, J=7.8 Hz, 2H).

Example 111

A solution of Example 111a (100 mg, 0.26 mmol), Example 111 b (96 mg,0.76 mmol), Pd₂(dba)₃ (24 mg, 0.026 mmol), Xantphos (8 mg, 0.013 mmol)and Cs₂CO₃ (170 mg, 0.52 mmol) in dioxane (3 mL) was heated to 110° C.for 2 h in Ar atmosphere. This mixture was filtered and directlypurified by prep-HPLC to afford Example 111 (37 mg, 30.1% yield) as ayellow solid. LCMS [M+1]⁺=471.3. ¹H NMR (400 MHz, DMSO-d₆) δ 11.07 (s,1H), 10.21 (s, 1H), 9.10 (s, 1H), 8.54 (s, 1H), 8.14 (s, 1H), 7.64 (dd,J=13.6, 7.9 Hz, 2H), 7.27 (t, J=7.9 Hz, 1H), 7.08 (s, 1H), 3.92 (s, 3H),3.69 (s, 3H), 3.01-2.92 (m, 1H), 2.34 (s, 3H), 2.27 (s, 3H), 1.11-0.96(m, 4H).

Example 112

A solution of Example 112a (100 mg, 0.26 mmol,), Example 112b (80 mg,0.78 mmol), Pd₂(dba)₃ (24 mg, 0.026 mmol, Xantphos (8 mg, 0.013 mmol)and Cs₂CO₃ (170 mg, 0.52 mmol) in dioxane (3 mL) was heated to 110° C.for 2 h in Ar atmosphere. This mixture was filtered and directlypurified by prep-HPLC to afford Example 112 (34 mg, 28.6% yield) as ayellow solid. LCMS [M+1]⁺=456.2. ¹H NMR (400 MHz, DMSO-d₆) δ 11.12 (s,1H), 9.91 (s, 1H), 9.06 (s, 1H), 8.53 (s, 1H), 8.25 (s, 1H), 7.68 (d,J=8.0 Hz, 1H), 7.60 (d, J=7.8 Hz, 1H), 7.52 (t, J=7.8 Hz, 1H), 7.26 (t,J=7.9 Hz, 1H), 7.15 (d, J=8.3 Hz, 1H), 6.73 (d, J=7.3 Hz, 1H) 3.92 (s,3H), 3.69 (s, 3H), 2.98-2.89 (m, 1H), 2.28 (s, 3H), 1.09-0.94 (m, 4H).

Example 113

A solution of Example 113a (100 mg, 0.26 mmol,), Example 113b (30 mg,0.26 mmol), Pd₂(dba)₃ (24 mg, 0.026 mmol), Xantphos (8 mg, 0.013 mmol)and Cs₂CO₃ (170 mg, 0.52 mmol) DMA (3 mL) was heated to 130° C. for 2 hin Ar atmosphere. This mixture was filtered and directly purified byprep-HPLC to afford Example 113 (13 mg, 10.9% yield) as a yellow solid.LCMS [M+1]⁺=457.2. ¹H NMR (400 MHz, DMSO-d₆) δ 11.04 (s, 1H), 10.21 (s,1H), 9.09 (s, 1H), 8.54 (s, 1H), 7.97 (d, J=9.1 Hz, 1H), 7.62 (dd,J=15.5, 8.4 Hz, 3H), 7.43 (d, J=9.2 Hz, 1H), 7.25 (t, J=8.0 Hz, 1H),3.93 (s, 3H), 3.70 (s, 3H), 2.94 (t, J=5.6 Hz, 1H), 1.09-0.96 (m, 4H).

Example 114

Step 1: Example 114b

To a solution of Example 114a (500 mg, 1.24 mmol, 1.0 eq) in THF (15 mL)was added EtMgBr (9.93 mL, 1.0 M in THF, 9.93 mmol, 5.0 eq) dropwise at−10 ° C. The reaction solution was stirred for 30 min at r.t. Thereaction solution was poured into saturated aqueous of NH₄Cl (20 mL) at0° C., extracted with EtOAc (20 mL*3), the combined organic layers werewashed with brine (20 mL), dried over Na₂SO₄ and concentrated. Theresidue was purified by silica gel flash column chromatography, elutedwith DCM/MeOH (10/1) to afford desired product Example 114b (367 mg,79.5% yield) as a yellow solid. LCMS [M+1]⁺=372.3.

Step 2: Example 114

To a solution of Example 114b (100 mg, 0.27 mmol, 1.0 eq) in dioxane (5mL) were added Example 114c (81 mg, 0.81 mmol, 3.0 eq), Cs₂CO₃ (17.5 mg,0.54 mmol, 2.0 eq), and 3^(rd) t-Bu-Xphos Pd (24 mg, 0.027 mmol, 0.1eq). The reaction was stirred for 4 h at 110° C. under N₂. The mixturewas filtered and the filtrate was concentrated. The crude product waspurified by Prep-TLC (DCM/MeOH=15/1) to give the desired product Example114 (43.7 mg, 37.3% yield) as a yellow solid. LCMS [M+1]⁺=436.3. ¹H NMR(300 MHz, DMSO-d₆) δ 11.03 (s, 1H), 9.16 (s, 1H), 8.81 (s, 1H), 8.57 (s,1H), 7.90 (s, 1H), 7.63 (dd, J=7.8, 1.5 Hz, 1H), 7.54 (dd, J=7.8, 1.5Hz, 1H), 7.26 (t, J=8.1 Hz, 1H), 4.03-3.92 (m, 7H), 3.73 (s, 3H), 3.10(q, J=7.2 Hz, 2H), 2.21-2.08 (m, 2H), 1.13 (t, J=7.2 Hz, 3H).

Example 115

To a solution of Example 115a (100 mg, 0.27 mmol, 1.0 eq) in dioxane (5mL) were added Example 115b (103 mg, 0.81 mmol, 3.0 eq), Cs₂CO₃ (175 mg,0.54 mmol, 2.0 eq), Xantphos (31 mg, 0.054 mmol, 0.2 eq) andPd₂(dba)₃CHCl₃ (28 mg, 0.027 mmol, 0.1 eq). The reaction mixture wasstirred for 4 h at 110° C. under N₂. The mixture was filtered and thefiltrate was concentrated. The crude product was purified by Prep-TLC(DCM/MeOH=15/1) to give the desired product Example 115 (40.3 mg, 32.3%yield) as a light yellow solid. LCMS [M+1]⁺=464.3. ¹H NMR (300 MHz,DMSO-d₆) δ 10.96 (s, 1H), 8.89 (s, 1H), 8.56 (s, 1H), 8.15 (s, 1H), 7.62(dd, J=7.8, 1.5 Hz, 1H), 7.56 (dd, J=7.8, 1.5 Hz, 1H), 7.26 (t, J=7.8Hz, 1H), 4.09-3.96 (m 3H), 3.95 (s, 3H), 3.72 (s, 3H), 3.39 (t, J=8.1Hz, 2H), 3.10 (q, J=7.2 Hz, 2H), 1.19-1.03 (m, 9H).

Example 116

To a solution of Example 116a (100 mg, 0.27 mmol, 1.0 eq) in dioxane (5mL) were added Example 116b (69 mg, 0.81 mmol, 3.0 eq), Cs₂CO₃ (175 mg,0.54 mmol, 2.0 eq), Xantphos (31 mg, 0.054 mmol, 0.2 eq) andPd₂(dba)₃CHCl₃ (28 mg, 0.027 mmol, 0.1 eq). The reaction solution wasstirred for 4 h at 110° C. under N₂. The reaction solution was filteredand the filtrate was concentrated. The crude product was purified byPrep-TLC (DCM/MeOH=15/1) to give the desired product Example 116 (40.7mg, 36.0% yield) as a light yellow solid. LCMS [M+1]⁺=421.3. ¹H NMR (300MHz, DMSO-d₆) δ 11.04 (s, 1H), 10.90 (s, 1H), 8.88 (s, 1H), 8.56 (s,1H), 8.00 (s, 1H), 7.65 (dd, J=7.8, 1.5 Hz, 1H), 7.52 (dd, J=7.8, 1.5Hz, 1H), 7.26 (t, J=7.8 Hz, 1H), 3.95 (s, 3H), 3.71 (s, 3H), 3.12 (q,J=7.2 Hz, 2H), 2.07-1.96 (m, 1H), 1.13 (t, J=7.2 Hz, 3H), 0.79 (d, J=6.0Hz, 4H).

Example 117

Step 1: Example 117b

To a solution of dimethyl 3-oxopentanedioate (5.0 g, 28.7 mmol)) andNi(acac)₂ (738 mg, 2.87 mmol) in dioxane (30 mL) was added NH₂—CN (3.6g, 86.2 mmol). The mixture was stirred at 110° C. for o.n. The reactionwas cooled to r.t. The mixture was filtered and the filter cake wascollected, washed with MeOH (20 mL) and concentrated in vacuo to givethe desired product Example 117b (3.0 g, 56.6% yield) as a yellow solid.LCMS [M+1]⁺=185.0

Step 2: Example 117c

To a solution of Example 117b (2.5 g, 13.58 mmol) in POCl₃ (15 mL) wasadded DIEA (2 mL) at 0° C., which was heated to 30° C. and stirred foro.n. The reaction was concentrated in vacuo H₂O (15 mL) and MeOH (3 mL)were added at 0° C. which was stirred at r.t. for 1 h. The mixture wasfiltered and the filtrate cake was collected by filtration to giveExample 117c (1.5 g, 50.1% yield) as a yellow solid. LCMS [M+1]⁺=221.0

Step 3: Example 117e

To a solution of Example 117c (12 g, 5.42 mmol) and Example 117d (1.21g, 5.96 mmol) in EtOH (30 mL) was added conc. HCl (5 mL) and thesolution was heated to reflux for o.n. The reaction was concentrated invacuo. The residue was dissolved in EtOAc (100 mL) and H₂O (50 mL), andthe pH was adjusted to ˜8 with sat. NaHCO₃. The organic layer wasseparated and concentrated. The residue was purified by silica gelchromatography (DCM/MeOH=30/1) to afford the product Example 117e (700mg, 33.1% yield) as a yellow solid. LCMS [M+1]⁺=389.11.

Step 4: Example 117f

To a solution of Example 117e (690 mg, 1.78 mmol) in THF (30 mL) and H₂O(10 mL) cooled at 0° C. was added LiOH.H₂O (112 mg, 2.67 mmol) and thesolution was stirred at r.t. for o.n. The reaction was concentrated invacuo. The residue was dissolved in H₂O (50 mL), adjusted pH ˜4 with HCl(2 mol/L), and extracted with EtOAc (100 mL). The organic layer wasconcentrated to afford the crude product Example 117f (750 mg, 100%crude yield) as a yellow solid. LCMS [M+1]⁺=375.2

Step 5: Example 117g

To a solution of Example 117 (500 mg, 1.33 mmol) in DMF (10 mL) wereadded DIEA (515 mg, 3.99 mmol), HATU (610 mg, 1.60 mmol) and CD₃—NH₂.HCl(110 mg, 1.59 mmol) and the solution was stirred at r.t. for 2 h. Thereaction was diluted with EtOAc (50 mL), washed with brine (10 mL* 3),dried over Na₂SO₄, and concentrated in vacuo. The residue was purifiedby silica gel chromatography (DCM/MeOH=30/1) to afford the productExample 117g (510 mg, 98% yield) as a light yellow solid. LCMS[M+1]⁺=391.0

Step 6: Example 117

To a mixture of Example 117g (500 mg, 1.278 mmol), Example 117h (33 mg,1.917 mmol) and Cs₂CO₃ (167 mg, 2.55 mmol) in dioxane (5 mL) was added3^(rd)t-Bu-Xphos-Pd (22.5 mg, 0.128 mmol). The mixture was degassed withN₂ three times, then heated to 100° C. and stirred for overnight. Thereaction was concentrated in vacuo. The residue was further purified byprep-HPLC to give the desired product Example 117 (60 mg, 54.2% yield)as a white solid. LCMS [M+1]⁺=440.1. ¹H NMR (300 MHz, DMSO-d₆) δ 9.29(s, 1H), 8.56 (s, 1H), 8.43 (s, 1H), 7.74 (d, J=6.8 Hz, 1H), 7.39 (d,J=7.6 Hz, 1H), 7.29 (t, J=7.8 Hz, 1H), 3.94 (s, 3H), 3.70 (s, 3H),1.65-1.80 (m, 1H), 0.8-0.94 (m, 4H).

Example 118

To the solution of Example 118a (100 mg, 0.26 mmol, 1.0 eq) dioxane (5mL) were added Example 118b (95 mg, 0.78 mmol, 3.0 eq), Cs₂CO₃ (170 mg,0.52 mmol, 2.0 eq), Xantphos (15 mg, 0.026 mmol, 0.1 eq) andPd₂(dba)₃.CHCl₃ (27 mg, 0.026 mmol, 0.1 eq). The reaction solution wasstirred for 4 h at 110° C. under N₂. The reaction solution was filteredand the filtrate was concentrated. The crude product was purified byPrep-TLC (DCM/MeOH=15/1) to afford the desired product Example 118 (21.9mg, 17.9% yield) as a light yellow solid. LCMS [M+1]⁺=469.3. ¹H NMR (300MHz, DMSO-d₆) δ 10.94 (s, 1H), 9.04 (s, 1H), 8.59 (s, 1H), 7.69 (dd,J=7.8, 1.8 Hz, 1H), 7.52 (dd, J=7.8, 1.5 Hz, 1H), 7.30 (t, J=7.8 Hz,1H), 6.64 (s, 1H), 3.95 (s, 3H), 3.69 (s, 3H), 3.00-2.89 (m, 1H), 1.22(s, 9H), 1.13-1.00 (m, 4H).

Example 119

Step 1: Example 119

To a solution of Example 119a (100 mg, 0.26 mmol) and Example 119b (44mg, 0.39 mmol) in 1,4-dioxane (2 mL) were added Pd₂(dba)₃ (24 mg, 0.026mmol), xantphos (30 mg, 0.052 mmol) and Cs₂CO₃ (170 mg, 0.52 mmol). Themixture was degassed by nitrogen for 3 times and stirred at 110° C. for2 h. When completed, the reaction was cooled to r.t., diluted with MeOH(5 mL) and filtered. The filtrate was purified directly by Prep-HPLC togive the desired product Example 119 (19.7 mg, 16.6% yield) as a yellowsolid. LCMS [M+1]⁺=460.0. ¹H NMR (400 MHz, DMSO-d₆) δ 11.05 (s, 1H),9.40 (s, 1H), 9.06 (s, 1H), 8.54 (s, 1H), 8.05 (d, J=4.6 Hz, 1H), 7.92(s, 1H), 7.65 (q, J=8.1, 5.8 Hz, 2H), 7.59 (d, J=7.8 Hz, 1H), 7.29 (t,J=8.0 Hz, 1H), 7.04 (dt, J=8.0, 3.9 Hz, 1H), 3.93 (s, 3H), 3.69 (s, 3H),2.95 (dt, J=8.1, 3.71 Hz, 1H), 1.07 (t, J=3.7 Hz, 2H), 0.99 (dd, J=7.9,4.5 Hz, 2H).

Example 120

Step 1: Example 120b

To a solution of Example 120a (5.37 g, 47.9 mmol, 1.0 eq) in ACN (250mL) was added NBS (6.2 g, 52.7 mmol, 1.1 eq) at 0° C. under N₂protection. The reaction solution was stirred at r.t. for 1 h, and thenthe mixture was concentrated. The residue was purified by silica gelflash column chromatography (Petroleum Ether/EtOAc=5/1) to afford theproduct Example 120b (6.8 g, 75% yield) as a white solid. LCMS[M+1]⁺=190.2.

Step 2: Example 120c

To a solution of Example 120b (6.0 g, 31.4 mmol, 1.0 eq) in dry THF (150mL) was added n-BuLi (44 mL, 2.5 M in THF, 110 mmol, 3.5 eq) dropwise at−78° C. under N₂ protection. The mixture was stirred for 5 min at thesame temperature. Acetone (18.2 g, 314 mmol, 10.0 eq) in THF (50 mL) wasadded dropwise at −78° C. under N₂ protection. The mixture was warmed tor.t. and stirred for 30 min. The reaction was poured into saturatedaqueous NH₄Cl (100 mL) and extracted with EtOAc (200 mL*2). The combinedorganic layers were washed with brine, dried over anhydrous Na₂SO₄, andconcentrated. The crude product was purified by silica gel flash columnchromatography (Petroleum Ether/EtOAc=5/1) to afford the product Example120c (3.5 g, 65% yield) as a green solid. LCMS [M+1]⁺=171.2.

Step 3: Example 120

To a solution of Example 120d (100 mg, 0.26 mmol, 1.0 eq,) in dioxane (3mL) were added Cs₂CO₃ (169 mg, 0.52 mmol, 2.0 eq), Example 120c (132 mg,0.77 mmol, 3.0 eq), Xaraphos (29 mg, 0.05 mmol, 0.2 eq) andPd₂(dba)₃.CHCl₃ (31 mg, 0.03 mmol, 0.1 eq). The reaction mixture wasstirred for 3 h at 110 ° C. under N₂ protection. After cooled to roomtemperature, the solvent was removed, the crude product was purified byPrep-TLC (DCM/MeOH=1.5/1) to afford the product Example 120 (48.4 mg,36% yield) as an off-white solid. LCMS [M+1]⁺=518.4. ¹H NMR (300 MHz,DMSO-d₆) δ 11.11 (s, 1H), 10.14 (s, 1H), 9.11 (s, 1H), 8.56 (s, 1H),7.97 (dd, J=10.8, 8.4 Hz, 1H), 7.80 (s, 1H), 7.73 (dd, J=7.8, 1.5 Hz,1H), 7.62 (dd, J=7.8, 1.8 Hz, 1H), 7.49 (dd, J=8.1, 1.8 Hz, 1H), 7.27(t, J=7.8 Hz, 1H), 5.26 (s, 1H), 3.95 (s, 3H), 3.72 (s, 3H), 3.05-2.90(m, 1H), 1.46 (s, 6H), 1.16-0.94 (m, 4H).

Example 121

Step 1: Example 121c

To a solution of Example 121a (200 mg, 1.5 mmol, 1.0 eq) in dioxane (3mL) was added Example 121b (265.5 mg, 4.5 mmol, 3.0 eq). The reactionsolution was stirred for 16 h at r.t. and concentrated to dryness. Theresidue was suspended in DCM and sonicated. The resulting solid wascollected by filtration to afford Example 121c (57 mg, 37% yield) as awhite solid.

Step 2: Example 121

To a solution of Example 121d (60 mg, 0.16 mmol, 1.0 eq,) and Example121c (49 mg, 0.48 mmol, 3.0 eq) in dioxane (2 mL) were addedCs₂CO₃(104.3 mg, 0.32 mmol, 2.0 eq), Xantphos (17.4 mg, 0.03 mmol, 0.2eq) and Pd₂(dba)₃.CHCl₃ (20.7 mg, 0.02 mmol, 0.1 eq). The reactionmixture was stirred at 110° C. for 4 h under N₂ protection. After cooledto room temperature, the solvent was removed, and the crude product waspurified by Prep-TLC (DCM/MeOH=15/1) to afford the product Example 121(40.1 mg, 56% yield) as a yellow solid. LCMS [M+1]⁺=450.4. ¹H NMR (300MHz, DMSO-d₆) δ 10.97 (s, 1H), 9.13 (s, 1H), 9.05 (s, 1H), 8.56 (s, 1H),7.76 (d, J=7.5 Hz, 1H), 7.63 (dd, J=7.8, 1.5 Hz, 1H), 7.53 (dd, J=7.8,1.5 Hz, 1H), 7.39 (s, 1H), 7.26 (t, J=7.8 Hz, 1H), 3.95 (s, 3H),3.86-3.73 (m, 1H), 3.70 (s ,3H),3.00-2.88 (m, 1H), 1.16-0,95 (m, 10H).

Example 122

Step 1: Example 122b

To a solution of Example 122a (700 mg, 4.61 mmol) in THF (65 mL) wasadded MeMgCl (15 mL, 45 mmol) at 0° C. under argon protection. Thereaction mixture was allowed to warm to room temperature and stirred for16 h. Then the mixture was quenched by aq. NH₄Cl, extracted with EA (50mL*2). The combined organic phase was washed by water, brine and driedover anhydrous Na₂SO₄. The solvent was removed under reduced pressure togive Example 122b (600 mg, 85.7% yield) as brown oil, which was used forthe next step directly.

Step 1: Example 122

To a solution of Example 122c (100 mg, 0.26 mmol,) and Example 122b (59mg, 0.39 mmol) in 1,4-dioxane (2.5 mL) were added Pd₂(dba)₃ (24 mg,0.026 mmol), Xantphos (30 mg, 0.052 mmol) and Cs₂CO₃ (170 mg, 0.52mmol). The mixture was degassed by nitrogen for 3 times and stirred at110° C. for 2 h. When completed, the reaction was cooled to r.t.,diluted with MeOH (5 mL) and filtered. The filtrate was purifieddirectly by Prep-TLC (DCM/MeOH=15/1) to give the desired product Example122 (16 mg, 11.5% yield) as a yellow solid. LCMS [M+1]⁺=500.0. ¹H NMR(400 MHz, DMSO-d₆) δ 11.05 (s, 1H), 9.90 (s, 1H), 9.06 (s, 1H), 8.54 (s,1H), 8.25 (s, 1H), 7.95 (s, 1H), 7.72 (d, J=8.8 Hz, 1H), 7.67 (d, J=8.0Hz, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.50 (d, J=8.8 Hz, 1H), 7.28 (t, J=8.0Hz, 1H), 3.93 (s, 3H), 3.70 (s, 3H), 2.94 (s, 1H), 1.40 (s, 6H), 1.05(s, 2H), 0.98 (d, J=7.7 Hz, 2H).

Example 123

To the solution of Example 123a (100 mg, 0.26 mmol, 1.0 eq) in dioxane(5 mL) were added Example 123b (95 mg, 0.78 mmol, 3.0 eq), Cs₂CO₃ (170mg, 0.52 mmol, 2.0 eq), Xantphos (15 mg, 0.026 mmol, 0.1 eq) andPd₂(dba)₃.CHCl₃ (27 mg, 0.026 mmol, 0.1 eq). The reaction mixture wasstirred for 4 h at 110° C. under N₂. The reaction solution was filteredand the filtrate was concentrated. The crude product was purified byPrep-TLC (DCM/MeOH=15/1) to afford the desired product Example 123 (26.1mg, 21.4% yield) as a light yellow solid. LCMS [M+1]⁺=469.3. ¹H NMR (300MHz, DMSO-d₆) δ 10.89 (s, 1H), 9.05 (s, 1H), 8.91 (brs, 1H), 8.56 (s,1H), 7.67 (dd, J=7.8, 1.5 Hz, 1H), 7.52 (dd, J=8.1, 1.8 Hz, 1H), 7.29(t, J=8.1 Hz, 1H), 6.64 (s, 1H), 3.95 (s, 3H), (s, 3H), 3.00-2.88 (m,1H), 1.22 (s, 9H), 1.12-0.99 (m, 4H).

Example 124

Step 1: Example 124c

To a solution of Example 124b (465 mg, 5.28 mmol, 1.5 eq) in DMF (10 mL)was added Cs₂CO₃ (2.3 g, 7.04 mmol, 2.0 eq). The reaction mixture wasstirred for 10 min at r.t., followed by addition of Example 124a (500mg, 3.52 mmol, 1.0 eq) in DMF (3 mL). The mixture was stirred for 4 h at80° C. After cooled to room temperature, the mixture was poured into H₂O(25 mL) and extracted with EtOAc (50 mL*2). The combined organic layerswere washed with brine, dried over Na₂SO₄and concentrated. The residuewas purified by silica gel flash column chromatography, eluted withPetroleum Ether/EtOAc (1/1) to afford the product Example 124c (250 mg,32% yield) as a yellow solid. LCMS [M+1]⁺=211.2.

Step 2: Example 124d

To a solution of Example 124c (250 mg, 1.19 mmol, 1.0 eq) in MeOH (30mL) was added Pd/C (25 mg) under N₂ protection. The suspension wasdegassed under vacuum and purged with H₂ three times, and the reactionmixture was stirred at r.t. for 0.5 h under H₂ balloon. The solid wasfiltered out, and the filtrate was concentrated to afford the productExample 124d (230 mg, crude, yield: quant.) as yellow oil. LCMS[M+1]⁺=181.2.

Step 3: Example 124

To a solution of Example 124e (100 mg, 0.26 mmol, 1.0 eq,) in dioxane (3mL) were added Cs₂CO₃ (169.5 mg, 0.52 mmol, 2.0 eq), Example 124d (93.7mg, 0.52 mmol, 2.0 eq) and 3^(rd)-t-Bu-xphos-Pd (26.7 mg, 0.03 mmol, 0.1eq). The reaction mixture was stirred for 4 h at 110° C. under N₂protection. After cooled to room temperature, the solvent was removed,and the crude product was purified by Prep-TLC (DCM/MeOH=15/1) to affordthe product Example 124 (37.0 mg, 27% yield) as a yellow solid. LCMS[M+1]⁺=528.3. ¹H NMR (300 MHz, DMSO-d₆) δ 11.06 (s, 1H), 9.87 (s, 1H),9.07 (s, 1H), 8.56 (s, 1H), 7.90 (d, J=3.0 Hz, 1H), 7.76 (s, 1H), 7.67(dd, J=7.8, 1.5 Hz, 1H), 7.63-7.55 (m, 2H), 7.40 (dd, J=9.0, 3.0 Hz,1H), 7.32 (t, J=7.8 Hz, 1H), 5.08-4.99 (m, 1H), 3.95 (s, 3H), 3.91-3.75(m, 4H), 3.72 (s, 3H), 3.00-2.88 (m, 1H), 2.29-2.05 (m, 1H), 2.03-1.89(m, 1H), 1.15-0.91 (m, 4H).

Example 125

Step 1: Example 125b

To a solution of Example 125a (5.0 g, 35.2 mmol, 1.0 eq) in DMF (50 mL)was added NaSMe (18.5 g, 20% in water, 53 mmol, 1.5 eq) dropwise at 0°C. The reaction mixture was stirred for 1 h at r.t. The reaction wasdiluted with EtOAc (100 mL) and washed with brine. The organic layer wasdried over Na₂SO₄ and concentrated. The residue was purified by silicagel flash column chromatography, eluted with Petroleum Ether/EtOAc (2/1)to afford the product Example 125b (4.9 g, 82% yield) as a yellow solid.LCMS [M+1]⁺=171.2.

Step 2: Example 125c

To a solution of Example 125b (4.8 g, 28 mmol, 1.0 eq) in MeOH (100 mL)were added Fe powder (7.9 g, 141 mmol, 5.0 eq), NH₄Cl (7.5 g, 141 mmol,5.0 eq) and AcOH (3 mL). The reaction mixture was stirred for 1 h at 80°C. The reaction mixture was basified with K₂CO₃ (pH=7˜8). The solid wasfiltered out, and the filtrate was concentrated. The crude product waspurified by silica gel flash column chromatography, eluted withPetroleum Ether/EtOAc (2/1) to afford the product Example 125c (3.6 g,92% yield) as red oil.

LCMS [M+1]⁺=141.2.

Step 3: Example 125f

To a solution of Example 125d (5.0 g, 21 mmol, 1.0 eq) in dry THF (50mL) was added Example 125e (105 mL, 1.0 M in THF, 105 mmol, 5.0 eq)dropwise at −15° C. under N₂ protection. The mixture was stirred for 0.5h at r.t. The mixture was poured into saturated aqueous of NH₄Cl (100mL) and extracted with EtOAc (150 mL*2). The combined organic layerswere washed with brine, dried over Na₂SO₄ and concentrated. The residuewas purified by silica gel flash column chromatography, eluted withPetroleum Ether/EtOAc (10/1) to afford the product Example 125f (2.8 g,62% yield) as yellow oil. LCMS [M+1]⁺=216.2

Step 4: Example 125g

To a solution of Example 125c (500 mg, 3.57 mmol, 1.0 eq) in DMF (10mL), was added NaH (1.43 g, 60% in mineral oil, 35.7 mmol, 10.0 eq) inportions at 0° C. After addition, the reaction was stirred for 30 min at0° C., followed by addition of Example 125f (768 mg, 3.57 mmol, 1.0 eq)in DMF. The reaction mixture was stirred for 1 h at r.t. The reactionsolution was poured into water, extracted with EtOAc (50 mL*2), and thecombined organic layer dried over Na₂SO₄ and concentrated. The crudeproduct was purified by silica gel flash column chromatography, elutedwith Petroleum Ether/EtOAc (3/1) to afford the product Example 125g (370mg, 32% yield) as a yellow solid. LCMS [M+1]⁺=320.1

Step 5: Example 125h

To a solution of Example 125g (200 mg, 0.627 mmol, 1.0 eq) in DCM (4 mL)was added m-CPBA (434 mg, 2.51 mmol, 4.0 eq) at 0° C. The reactionmixture was stirred for 1 h at r.t. The reaction was diluted with DCM(50 mL), washed with NaOH aqueous solution (1M), Na₂SO₃ aqueous solutionand brine. The organic layer was dried over Na₂SO₄ and concentrated. Theresidue was purified by silica gel flash column chromatography, elutedwith Petroleum Ether/EtOAc (1/1) to afford the product Example 125h (60mg, 27% yield) as a yellow solid. LCMS [M+1]⁺=352.2.

Step 6: Example 125

To a solution of Example 125h (50 mg, 0.142 mmol, 1.0 eq) in dioxane (2mL) were added Cs₂CO₃ (93 mg, 0.285 mmol, 2.0 eq), Example 125i (27 mg,0.285 mmol, 2.0 eq), Xantphos (17 mg, 0.028 mmol, 0.2 eq) andPd₂(dba)₃.CHCl₃ (15 mg, 0.014 mmol, 0.1 eq). The reaction mixture wasstirred for 4 h at 110° C. under N₂ protection. After cooled to roomtemperature, the solvent was removed, and the crude product was purifiedby Prep-TLC (DCM/MeOH=15/1) to afford the product Example 125 (17 mg,29% yield) as a yellow solid. LCMS [M+1]⁺=411.2. ¹H NMR (300 MHz,DMSO-d₆) δ 11.83 (s, 1H), 10.54 (s, 1H), 9.18 (s, 1H), 8.86-8.78 (m,2H), 8.62 (dd, J=4.8, 2.1 Hz, 1H), 8.28 (dd, J=7.8, 2.1 Hz, 1H), 8.17(dd, J=9.3, 1.5 Hz, 1H), 7.61 (dd, J=9.3, 4.8 Hz, 1H), 7.33 (dd, J=7.8,4.8 Hz, 1H), 3.31 (s, 3H), 3.03-2.90 (m, 1H), 1.16-0.99(m, 4H).

Example 126

Step 1: Example 126c

To a solution of Example 126a (1.54 g, 7.1 mmol, 1.0 eq) in DMF (20 mL),was added NaH (2.86 g, 60% in mineral oil, 71 mmol, 10.0 eq) in portionsat 0° C. Example 126b (1.0 g, 7.1 mmol, 1.0 eq) in DMF was added to thesolution. The reaction mixture was stirred for 1 h at r.t. The reactionwas poured into water (100 mL), extracted with EtOAc (100 mL*3), and thecombined organic layers were dried over Na₂SO₄ and concentrated. Thecrude product was purified by silica gel flash column chromatography,eluted with Petroleum Ether/EtOAc (3/1) to afford the product Example126c (570 mg, 25% yield) as a yellow solid. LCMS [M+1]⁺=320.1

Step 2: Example 126d

To a solution of Example 126c (740 mg, 2.32 mmol, 1.0 eq) in DCM (8 mL)was added m-CPBA (1.61 g, 9.28 mmol, 4.0 eq) at 0° C. The reactionmixture was stirred for 2 h at r.t. The reaction was diluted with DCM(20 mL), washed with NaOH aqueous solution (1M), Na₂SO₃ aqueous solutionand brine. The organic layer was dried over Na₂SO₄, and concentrated.The residue was purified by silica gel flash column chromatography,eluted with Petroleum Ether/EtOAc (1/1) to afford the product Example126d (470 mg, 57% yield) as a yellow solid. LCMS [M+1]⁺=352.2.

Step 3: Example 126

To a solution of Example 126d (100 mg, 0.285 mmol, 1.0 eq) in dioxane (2mL) were added Cs₂CO₃ (186 mg, 0.57 mmol, 2.0 eq), Example 126e (87 mg,0.57 mmol, 2.0 eq), BINAP (36 mg, 0.057 mmol, 0.2 eq) andPd₂(dba)₃.CHCl₃ (30 mg, 0.028 mmol, 0.1 eq). The reaction mixture wasstirred for 4 h at 110° C. under N₂ protection. After cooled to roomtemperature, the solvent was removed, and the crude product was purifiedby Prep-TLC (DCM/MeOH=15/1) to afford the product Example 126 (12 mg, 9%yield) as an off-white solid. LCMS [M+1]⁺=468.1. ¹H NMR (300 MHz,DMSO-d₆) δ 11.84 (s, 1H), 10.04 (s, 1H), 9.14 (s, 1H), 8.95 (s, 1H),8.69-8.63 (m, 1H), 8.35 (dd, J=2.7, 0.9 Hz, 1H), 8.26 (dd, J=7.8, 2.4Hz, 1H),7.78 (dd, J=8.7, 2.41 Hz, 1H), 7.68 (d, J=8.7 Hz, 1H), 7.32 (dd,J=7.8, 4.8 Hz, 1H), 5.09 (s, 1H), 3.31 (s, 3H), 3.01-2.88 (m, 1H), 1.45(s, 6H), 1.12-0.97 (m, 4H).

Example 127

Step 1: Example 127b

To a solution of Example 127a (550 mg, 2.32 mmol, 1.0 eq) in DCM (10 mL)was added BBr₃ (1.15 g, 4.64 mmol, 2.0 eq) at −20° C. The reactionmixture was stirred for 2 h at r.t. It was quenched with NaHCO₃ aqueoussolution (10 mL), extracted with DCM (20 mL*3). The combined organiclayer was washed with brine, dried over Na₂SO₄ and concentrated toafford the product Example 127b (500 mg, crude, 96% yield) as a brownsolid. LCMS [M+1]⁺=224.3.

Step 2: Example 127c

To a mixture of Example 127b (500 mg, 2.24 mmol, 1.0 eq) and K₂CO₃ (927mg, 6.72 mmol, 3.0 eq) in ACN (10 mL) was added CD₃I (487.2 mg, 3.36mmol, 1.5 eq). The reaction mixture was stirred for 6 h at 80° C. Aftercooled to room temperature, the solvent was removed. The crude productwas purified by silica gel flash column chromatography eluted withPE/EtOAc (1/3) to afford the product Example 127c (200 mg, 37% yield) asa yellow solid. LCMS [M+1]⁺=241.2.

Step 3: Example 127d

To a solution of Example 127c (200 mg, 0.84 mmol, 1.0 eq) in MeOH (20mL) was added Pd/C (20 mg) under N₂ protection, the suspension wasdegassed under vacuum and purged with H₂ three times, the reactionmixture was stirred at r.t. for 1 h under H₂ balloon. The solid wasfiltered out, the filtrate was concentrated to afford the productExample 127d (160 mg, 90% yield) as a yellow solid. LCMS [M+1]⁺=211.2.

Step 4: Example 127f

To a solution of Example 127e (170 mg, 0.72 mmol, 1.0 eq) and Example127d (151.2 mg, 0.72 mmol, 1.0 eq) in dry THF (6 mL) was added LiHMDS(1.4 mL, 1 M in THF, 1.44 mmol, 2.0 eq) dropwise at −20° C. under N₂protection. The reaction mixture was stirred for 0.5 hat r.t., and thenthe silica was added to the mixture and concentrated. The residue waspurified by silica gel flash column chromatography eluted with DCM/MeOH(20/1) to afford the product Example 127f (45 mg, 15% yield) as a yellowsolid. LCMS [M+1]⁺=409.4.

Step 5: Example 127h

To a solution of Example 127f (45 mg, 0.11 mmol, 1.0 eq) in THF (3 mL)was added Example 127g (0.9 mL, 1.0 M in THF, 0.88 mmol, 8.0 eq)dropwise at 0° C. under N₂ protection. The mixture was stirred for 0.5 hat r.t. The reaction was poured into saturated aqueous of NH₄Cl (10 mL)and extracted with EtOAc (15 mL×3). The combined organic layer waswashed with brine, dried over Na₂SO₄, and concentrated. The crudeproduct was purified by Prep-TLC (DCM/MeOH=15/1) to afford the productExample 127f (40 mg, 93% yield) as a yellow solid. LCMS [M+1]⁺=390.3.

Step 6: Example 127

To a solution of Example 127f (40 mg, 0.10 mmol, 1.0 eq) in dioxane (3mL) were added Cs₂CO₃ (65.2 mg, 0.20 mmol, 2.0 eq), Example 127l (26.2mg, 0.30 mmol, 3.0 eq), Xantphos (11.6 mg, 0.02 mmol, 0.2 eq) andPd₂(dba)₃.CHCl₃ (10.4 mg, 0.01 mmol, 0.1 eq). The reaction mixture wasstirred for 4 h at 110° C. under N₂ protection. After cooled to roomtemperature, the solvent was removed, the crude product was purified byPrep-TLC (DCM/MeOH=15/1) to afford the product Example 127 (3.1 mg, 7%yield) as a yellow solid. LCMS [M+1]⁺=439.3. ¹H NMR (300 MHz, DMSO-d₆) δ11.01 (s, 1H), 10.93 (s, 1H), 9.13 (s, 1H), 8.56 (s, 1H), 8.04 (s, 1H),7.64 (dd, J=7.8, 1.5 Hz, 1H), 7.52 (dd, J=8.1, 1.8 Hz, 1H), 7.26 (t,J=7.8 Hz, 1H), 3.08-2.90 (m, 1H), 2.11-1.93 (m, 1H), 1.18-0.98 (m, 4H),0.81 (d, J=6.0 Hz, 4H).

Example 128

To a solution of Example 128 (100 mg, 0.26 mmol, 1.0 eq) in dioxane (5mL) were added Example 128b (95 mg, 0.78 mmol, 3.0 eq), Cs₂CO₃ (170 mg,0.52 mmol, 2.0 eq), Xantphos (15 mg, 0.026 mmol, 0.1 eq) andPd₂(dba)₃.CHCl₃ (27 mg, 0.026 mmol, 0.1 eq). The reaction mixture wasstirred for 4 h at 110° C. under N₂. The reaction solution was filteredand the filtrate was concentrated. The crude product was purified byPrep-TLC (DCM/MeOH=15/1) to give 32.0 mg crude product (90% purity) andfurther purified by Prep-TLC (DCM/MeOH=15/1) to afford the desiredproduct Example 128 (12.1 mg, 9.9% yield) as a yellow solid. LCMS[M+1]⁺=469.3. ¹H NMR (300 MHz, DMSO-d₆) δ 10.89 (s, 1H), 9.04 (s, 1H),8.91 (brs, 1H), 8.56 (s, 1H), 7.67 (dd, J=7.8, 1.5 Hz, 1H), 7.53 (d,J=6.6 Hz, 1H), 7.29 (t, J=7.8 Hz, 1H), 6.64 (s, 1H), 3.95 (s, 3H), 3.69(s, 3H), 3.00-2.88 (m, 1H), 1.22 (s, 9H), 1.12-0.99 (m, 4H).

Example 129

Step 1: Example 129c

A solution of Example 129b (300 mg, 2.19 mmol) in 1,4-dioxane (5 mL) wastreated with Example 129a (353 mg, 3.28 mmol) and TEA (664 mg, 6.57mmol). The mixture was stirred at r.t. for 16 hrs. After reactioncompleted, the solvent was concentrated, the residue was suspended inDCM (5 mL), sonicated and the resulting solid was collected viafiltration, dried to afford the desired product Example 129c (253 mg,crude) as a white solid. LCMS [M+1]⁺=115.0.

Step 2: Example 129

To a solution of Example 129a (80 mg, 0.21 mmol) and Example 129c (29.3mg, 0.26 mmol) in 1,4-dioxane (2 mL) were added Pd₂(dba)₃ (19.6 mg,0.021 mmol), XantPhos (24.7 mg, 0.042 mmol) and Cs₂CO₃ (140 mg, 0.43mmol). The mixture was sealed, degassed by nitrogen for 3 times andstirred at 110° C. for 16 h. When completed, the reaction was cooled tor.t. and filtered. The filtrate was purified directly by Prep-HPLC togive the desired product Example 129 (21.8 mg, 22.7% yield) as a whitesolid. LCMS [M+1]⁺=452.0. ¹H NMR (400 MHz, DMSO-d₆) δ 10.89 (s, 1H),9.59 (s, 1H), 9.02 (d, J=5.3 Hz, 1H), 8.54 (s, 1H), 8.00 (s, 1H), 7.62(d, J=7.8 Hz, 1H), 7.49 (d, J=7.9 Hz, 1H), 7.24 (t, J=8.0 Hz, 1H), 4.09(s, 2H), 3.93 (s, 3H), 3.71 (s, 3H), 3.54 (s, 2H), 2.84 (d, J=4.4 Hz,3H), 2.59 (d, J=8.4 Hz, 1H), 1.15 (d, J=6.7 Hz, 3H).

Example 130

Step 1: Example 130c

To a solution of Example 130a (200 mg, 1.92 mmol) in acetone (4 mL) wasadded TEA (291 mg, 2.88 mmol) at 0-5° C., and then Example 130b (311 mg,2.88 mmol) was added dropwise. The mixture was stirred at roomtemperature for 1 h under N₂. The white solid was filtered off. To thefiltration was added NH₃—H₂O (5 eq.). The reaction mixture was stirredat room temperature overnight. The mixture was concentrated. The residuewas cooled and added Petroleum ether/EtOAc=1/1 (3 mL). The solid wascollected by filtered and dried to give Example 130c (17 mg, 8% yield)as a white solid.

Step 2: Example 130

To a solution of Example 130d (63 mg, 0.16 mmol) in dioxane (1.5 mL)were added Example 130c (17 mg, 0.16 mmol), Pd₂(dba)₃ (15 mg, 0.016mmol), Xantphos (10 mg, 0.016 mmol) and Cs₂CO₃ (108 mg, 0.33 mmol). Themixture was sealed and heated to 120° C. for 2 h. The mixture wasfiltrated and concentrated under reduced pressure. The residue waspurified by Prep-HPLC to give Example 130 (8.7 mg, 12% yield) as ayellow solid. LCMS [M+1]⁺=451.1. ¹H NMR (400 MHz, Chloroform-d) δ 11.12(s, 1H), 8.90 (s, 1H), 8.22-8.03 (m, 3H), 7.75 (d, J=7.8 Hz, 1H), 7.59(d, J=7.9 Hz, 1H), 7.25-7.22 (m, 1H), 4.78 (d, J=65.0 Hz, 1H), 3.99 (s,3H), 3.77 (s, 3H), 2.66-2.57 (m, 1H), 1.94-1.76 (m, 2H), 1.27-1.17 (m,3H), 1.07-1.0 (m, 2H).

Example 131

To a solution of Example 131a (40 mg, 0.104 mmol, 1.0 eq) and Example131b (35.4 mg, 0.208 mmol, 2.0 eq) in dioxane (3 mL) were added Xantphos(12.0 mg, 0.02 mmol, 0.2 eq), Cs₂CO₃ (67.8 mg, 0.208 mmol, 2.0 eq) andPd₂(dba)₃.CHCl₃ (10.4 mg, 0.01 mmol, 0.1 eq). The reaction mixture wasstirred at 110° C. for 4 h under N₂ protection. After cooled to roomtemperature, the solvent was removed, and the crude product was purifiedby Prep-TLC (DCM/MeOH=15/1) to afford the product Example 131 (7.4 mg,14% yield) as a yellow solid. LCMS [M+1]⁺=519.4.

¹H NMR (300 MHz, DMSO-d₆) δ 12.33 (s, 1H), 10.27 (s, 1H), 9.54 (s, 1H),9.18 (s, 1H), 8.66 (s, 1H), 8.17 (d, J=5.1 Hz, 1H), 8.05-7.95 (m, 1H),7.58 (d, J=8.1 Hz, 1H), 7.50 (d, J=5.1 Hz, 1H), 5.30 (s, 1H), 4.00 (s,3H), 3.88 (s, 3H), 3.08-2.93 (m, 1H), 1.50 (s, 6H), 1.16-0.98 (m, 4H).

Example 132

To a solution of Example 132a (100 mg, 0.26 mmol) and Example 132b (43mg, 0.39 mmol) in DMA (2.5 mL) were added Pd₂(dba)₃ (24 mg, 0.026 mmol),Xantphos (30 mg, 0.052 mmol) and Cs₂CO₃ (340 mg, 1.04 mmol). The mixturewas degassed by nitrogen for 3 times and stirred at 130° C. for 2 h.When completed, the reaction was cooled to r.t., diluted with MeOH (5mL) and filtered. The filtrate was purified directly by Prep-HPLC togive the desired product Example 132 (1.3 mg, 3.5% yield) as a whitesolid. LCMS [M+1]⁺=459.0. ¹H NMR (400 MHz, DMSO-d₆) δ 11.07 (s, 1H),9.49 (s, 1H), 8.97 (s, 1H), 8.53 (s, 1H), 8.30 (s, 0H), 7.65 (d, J=8.0Hz, 1H), 7.56 (d, J=8.0 Hz, 1H), 7.27 (t, J=7.9 Hz, 1H), 5.90 (s, 1H),3.92 (s, 3H), 3.68 (s, 3H), 3.57 (s, 3H), 2.88 (s, 1H), 2.17 (s, 3H),1.03 (s, 2H), 0.95 (d, J=7.7 Hz, 2H).

Example 133

To a solution of Example 133a (180 mg, 0.47 mmol,) and Example 133b (180mg, 1.41 mmol) in 1,4-dioxane (2 mL) were added Pd₂(dba)₃ (43 mg, 0.047mmol), xantphos (54 mg, 0.094 mmol) and Cs₂CO₃ (306 mg, 0.94 mmol). Themixture was degassed by nitrogen for 3 times, sealed and stirred at 120°C. for 16 h. When completed, the reaction was cooled to r.t., dilutedwith MeOH (5 mL) and filtered. The filtrate was purified directly byPrep-HPLC to give the desired product Example 133 (67.3 mg, 30.3% yield)as a white solid. LCMS [M+1]⁺=476.0. ¹H NMR (400 MHz, DMSO-d₆) δ 10.98(s, 1H), 9.19 (s, 1H), 9.02 (s, 1H), 8.54 (s, 1H), 7.90 (s, 1H), 7.60(d, J=7.8 Hz, 1H), 7.51 (d, J=8.0 Hz, 1H), 7.23 (t, J=8.0 Hz, 1H), 3.93(s, 3H), 3.67 (s, 3H), 3.64 (s, 4H), 2.94 (s, 1H), 1.18 (s, 6H), 1.06(d, J=4.5 Hz, 2H), 1.00 (d, J=7.8 Hz, 2H).

Example 134

To a solution of Example 134a (130 mg, 0.35 mmol) and Example 134b (67mg, 0.52 mmol) in 1,4-dioxane (4 mL) were added Pd₂(dba)₃ (32 mg, 0.035mmol), XantPhos (40 mg, 0.070 mmol) and Cs₂CO₃ (227 mg, 0.70 mmol). Themixture was sealed, degassed by nitrogen for 3 times and stirred at 110°C. for 16 h. When completed, the reaction was cooled to r.t. andfiltered. The filtrate was purified directly by Prep-HPLC to give thedesired product Example 134 (34 mg, 21.0% yield) as a yellow solid. LCMS[M+1]⁺=466.0. ¹H NMR (400 MHz, DMSO-d₆) δ 10.86 (s, 1H), 9.17 (d, J=5.3Hz, 1H), 8.55 (s, 1H), 8.27 (s, 1H), 7.62 (d, J=7.8 Hz, 1H), 7.51 (d,J=7.9 Hz, 1H), 7.25 (t, J=7.9 Hz, 1H), 4.06 (t, J=8.2 Hz, 2H), 4.02 (s,1H), 3.93 (s, 3H), 3.71 (s, 3H), 3.44 (t, J=8.1 Hz, 2H), 2.83 (d, J=4.6Hz, 3H), 1.09 (d, J=6.7 Hz, 6H).

Example 135

To a solution of Example 135a (100 mg, 0.26 mmol,) and Example 135b (43mg, 0.39 mmol) in 1,4-dioxane (2 mL) were added Pd₂(dba)₃ (24 mg, 0.026mmol), xantphos (30 mg, 0.052 mmol) and Cs₂CO₃ (170 mg, 0.52 mmol). Themixture was degassed by nitrogen for 3 times and stirred at 120° C. for16 h. When completed, the reaction was cooled to r.t., diluted with MeOH(5 mL) and filtered. The filtrate was purified directly by Prep-HPLC togive the desired product Example 135 (41.8 mg, 35.1% yield) as a whitesolid (contain 0.43 FA salt by ¹H NMR). LCMS [M+1]⁺=459.0. ¹H NMR (400MHz, DMSO-d₆) δ 13.32 (s, 1H), 10.96 (s, 1H), 9.20 (s, 1H), 8.54 (s,1H), 7.72 (d, J=6.6 Hz, 1H), 7.66 (d, J=7.8 Hz, 1H), 7.53 (d, J=7.9 Hz,1H), 7.27 (t, J=8.0 Hz, 1H), 6.99 (s, 1H), 5.84 (d, J=6.6 Hz, 1H), 3.93(s, 3H), 3.68 (s, 3H), 2.98 (d, J=7.1 Hz, 1H), 1.09 (d, J=4.3 Hz, 2H),1.03 (dd, J=9.6, 5.4 Hz, 2H).

Example 136

To a solution of Example 136a (100 mg, 0.26 mmol,) and Example 136b (37mg, 0.31 mmol) in 1,4-dioxane (1 mL) were added Pd₂(dba)₃ (24 mg, 0.026mmol), XantPhos (30 mg, 0.052 mmol) and Cs₂CO₃ (170 mg, 0.52 mmol). Themixture was degassed by nitrogen for 3 times and stirred at 110° C. for2 h. When completed, the reaction was cooled to r.t., diluted with MeOH(5 mL) and filtered. The filtrate was purified directly by Prep-HPLC togive the desired product Example 136 (4.5 mg, 3.7% yield) as a whitesolid. LCMS [M+1]⁺=467.2. ¹H NMR (400 MHz, DMSO-d₆) δ 11.00 (s, 1H),10.34 (s, 1H), 9.16 (s, 1H), 8.54 (s, 1H), 8.40 (d, J=8.0 Hz, 1H), 8.21(s, 1H), 7.6-7.60 (m, 3H), 7.31-7.27 (m, 2H), 3.93 (s, 3H), 3.69 (s,3H), 2.97 (br, 1H), 1.07-1.00 (m, 4H).

Example 137

To a solution of Example 137a (60 mg, 0.171 mmol, 1.0 eq) in dioxane (2mL) were added Cs₂CO₃ (111 mg, 0.342 mmol, 2.0 eq), Example 137b (32 mg,0.342 mmol, 2.0 eq), BINAP (21.3 mg, 0.034 mmol, 0.2 eq) andPd₂(dba)₃.CHCl₃ (17.7 mg, 0.017 mmol, 0.1 eq). The reaction mixture wasstirred for 4 h at 110° C. under N₂ protection. After cooled to roomtemperature, the solvent was removed, and the crude product was purifiedby Prep-TLC (DCM/MeOH=30/1) to afford the product Example 137 (8 mg, 11%yield) as an off-white solid. LCMS [M+1]⁺=410.2. ¹H NMR (300 MHz,DMSO-d₆) δ 11.85 (s, 1H), 10.11 (s, 1H), 9.16 (s, 1H), 9.03 (s, 1H),8.66 (dd, J=4.8, 1.8 Hz, 1H), 8.30-8.22 (m, 2H), 7.76-7.68 (m, 2H), 7.31(dd, J=7.8, 4.8 Hz, 1H), 6.99-6.91 (m, 1H), 3.12, (m, 3H), 3.01-2.89 (m,1H), 1.12-0.97 (m, 4H).

Example 138

To a solution of Example 138a (277 mg, 0.72 mmol) and Example 138b (84mg, 0.87 mmol) in 1,4-dioxane (4 mL) were added Pd₂(dba)₃ (66 mg, 0.072mmol), Xantphos (83 mg, 0.14 mmol) and Cs₂CO₃ (470 mg, 1.44 mmol). Themixture was degassed by nitrogen for 3 times and stirred at 110° C. for16 h. When completed, the reaction was cooled to r.t., diluted with MeOH(5 mL) and filtered. The filtrate was purified directly by Prep-HPLC togive the desired product Example 138 (21 mg, 6.6% yield) as a yellowsolid. LCMS [M+1]⁺=445.0. ¹H NMR (400 MHz, DMSO-d₆) δ 11.06 (s, 1H),9.60 (s, 1H), 8.99 (s, 1H), 8.54 (s, 1H), 7.65 (d, J=8.0 Hz, 1H), 7.56(d, J=8.1 Hz, 1H), 7.51 (s, 2H), 7.27 (t, J=7.9 Hz, 1H), 6.08 (s, 1H),3.92 (s, 3H), 3.69 (d, J=4.7 Hz, 6H), 2.89 (s, 1H), 1.03 (s, 2H), 0.95(s, 2H).

Example 139

To a solution of Example 139a (100 mg, 0.26 mmol) and Example 139b (37mg, 0.31 mmol) in 1,4-dioxane (1 mL) were added Pd₂(dba)₃ (24 mg, 0.026mmol), XantPhos (30 mg, 0.052 mmol) and Cs₂CO₃ (170 mg, 0.52 mmol). Themixture was degassed by nitrogen for 3 times and stirred at 110° C. for2 h. When completed, the reaction was cooled to r.t., diluted with MeOH(5 mL) and filtered. The filtrate was purified directly by Prep-TLC(MeOH/DCM=1/15) to give the desired product Example 139 (14.6 mg, 12.1%yield) as a white solid. LCMS [M+1]⁺=467.2. ¹H NMR (400 MHz, DMSO-d₆) δ11.04 (s, 1H), 10.53 (s, 1H), 9.13 (s, 1H), 8.61 (s, 1H), 8.54 (s, 1H),8.07 (d, J=12.0 Hz, 1H), 7.83-7.79 (m, 2H), 7.62 (t, J=8.0 Hz, 2H), 7.33(t, J=8.0 Hz, 1H), 3.93 (s, 3H), 3.69 (s, 3H), 2.97 (br, 1H), 1.21-1.01(m, 4H).

Example 140

To a solution of Example 140a (100 mg, 0.26 mmol,) and Example 140b (37mg, 0.31 mmol) in 1,4-dioxane (1 mL) were added Pd₂(dba)₃ (24 mg, 0.026mmol), Xantphos (30 mg, 0.052 mmol) and Cs₂CO₃ (170 mg, 0.52 mmol). Themixture was degassed by nitrogen for 3 times and stirred at 110° C. for2 h. When completed, the reaction was cooled to r.t., diluted with MeOH(5 mL) and filtered. The filtrate was purified directly by Prep-TLC(DCM/MeOH=15/1) to give the desired product Example 140 (12.2 mg, 10.1%yield) as a white solid. LCMS [M+1]⁺=467.2. ¹H NMR (400 MHz, DMSO-d₆) δ11.24 (s, 1H), 10.42 (s, 1H), 9.12 (s, 1H), 8.54 (s, 1H), 7.98 (s, 1H),7.87 (t, J=8.0 Hz, 1H), 7.78(d, J=8.0 Hz, 1H), 7.72 (d, J=8.0 Hz, 1H),7.58 (d, J=8.0 Hz, 1H), 7.52 (d, J=8.0 Hz, 1H), 7.35 (t, J=8.0 Hz, 1H),3.93 (s, 3H), 3.70 (s, 3H), 2.96 (br, 1H), 1.21-1.00 (m, 4H).

Example 141

Step 1: Example 141c

To a solution of Example 141a (182 mg, 1.94 mmol, 1.0 eq) in dioxane (10mL) were added Cs₂CO₃ (1.25 g, 3.87 mmol, 2.0 eq), Example 141b (500 mg,2.32 mmol, 1.2 eq), BINAP (240 mg, 0.387 mmol, 0.2 eq) andPd₂(dba)₃.CHCl₃ (199 mg, 0.194 mmol, 0.1 eq). The reaction mixture wasstirred for 4 h at 110° C. under N₂ protection. The solvent wasconcentrated, and the crude product was purified by silica gel flashcolumn chromatography, eluted with (DCM/MeOH=30/1) to afford the productExample 141c (490 mg, 72% yield) as a yellow solid. LCMS [M+1]⁺=293.1.

Step 2: Example 141e

To a solution of Example 141c (490 mg, 1.678 mmol, 1.0 eq) in THF (10mL) was added Example 141d (25.17 mL, 1.0 M in THF, 25.17 mmol, 15.0 eq)dropwise at 0° C. under N₂ protection. The mixture was stirred for 1.5 hat r.t. After the reaction was completed, the mixture was poured intosaturated aqueous of NH₄Cl (20 mL) and extracted with EtOAc (50 mL*2).The combined organic layers were washed with brine, dried over Na₂SO₄and concentrated. The residue was purified by silica gel flash columnchromatography, eluted with DCM/MeOH=(30/1) to afford the productExample 141e (170 mg, 37% yield) as a yellow solid. LCMS [M+1]⁺=274.1.

Step 3: Example 141

To a solution of Example 141e (60 mg, 0.22 mmol, 1.0 eq) in dioxane (2mL) were added Cs₂CO₃ (143 mg, 0.44 mmol, 2.0 eq), Example 141f (90 mg,0.44 mmol, 2.0 eq). 3rd-t-Bu-xphos-Pd (39 mg, 0.044 mmol, 0.2 eq). Thereaction mixture was stirred for 4 h at 110° C. under N₂ protection.After cooled to room temperature, the solvent was removed, the crudeproduct was purified by Prep-TLC (DCM/MeOH=20/1) to afford the productExample 141 (29 mg, 29% yield) as a yellow solid. LCMS [M+1]⁺=443.3. ¹HNMR (300 MHz, DMSO-d₆) δ 12.31 (s, 1H), 10.10 (s, 1H), 9.51 (s, 1H),9.17 (s, 1H), 8.66 (s, 1H), 8.35-8.32 (m, 1H), 8.19 (d, J=5.1 Hz, 1H),7.82-7.64 (m, 2H), 7.48 (d, J=5.1 Hz, 1H), 7.02-6.92 (m, 1H), 4.00 (s,3H), 3.88 (s, 3H), 3.06-2.95 (m, 1H), 1.67-0.97 (m, 4H).

Example 142

Step 1: Example 142c

A mixture of Example 142a (250 mg, 2.0 mmol), Example 142b (276 mg, 2.0mmol) and TEA (610 mg, 6.0 mmol) in 1,4-dioxane (2 mL) was stirred atroom temperature overnight. The reaction was filtered to give thedesired product Example 142c (350 mg, 51.4% yield) as a white solid.LCMS [M+1]⁺=133.1. ¹H NMR (400 MHz, DMSO-d₆) δ 5.97 (s, 2H), 3.88-3.75(m, 4H), 3.69 (s, 3H), 1.51 (d, J=24.0 Hz, 3H).

Step 2: Example 142

To a solution of Example 142c (40 mg, 0.31 mmol) and Example 142d (96mg, 0.25 mmol) in 1,4-dioxane (1 mL) were added Pd₂(dba)₃ (23 mg, 0.025mmol), Xantphos (29 mg, 0.051 mmol) and Cs₂CO₃ (166 mg, 0.51 mmol). Themixture was degassed by nitrogen for 3 times and stirred at 110° C. for2 h. When completed, the reaction was cooled to r.t., diluted with MeOH(5 mL) and filtered. The filtrate was purified directly by Prep-HPLC togive the desired product Example 142 (46.7 mg, 38.9% yield) as a yellowsolid. LCMS [M+1]⁺=473.2. ¹H NMR (400 MHz, DMSO-d₆) δ 10.90 (s, 1H),9.89 (s, 1H), 9.01 (s, 1H), 8.54 (s, 1H), 7.99 (s, 1H), 7.62 (d, J=8.0Hz, 1H), 7.49 (d, J=8.0 Hz, 1H), 7.25 (t, J=8.0 Hz, 1H), 4.13-4.01 (m,4H), 3.93 (s, 3H), 3.71 (s, 3H), 1.54 (d, J=24.0 Hz, 3H).

Example 143

Step 1: Example 143b

A solution of Example 143a (2.0 g, 15.5 mmol) in DMSO/H₂O (20 mL/20 mL)were treated with NaCN (1.52 g, 31.0 mmol) and DABCO (1.74 g, 15.5mmol). The mixture was stirred at 60° C. for 6 h. After reactioncompleted, the solvent was extracted by DCM (50 mL) and concentrated togive crude product, which was purified directly by Prep-HPLC to give thedesired product Example 143b (500 mg, 26.8% yield) as a white solid.LCMS [M+1]⁺=121.0

Step 2: Example 143

To a solution of Example 143b (60 mg, 0.5 mmol) and Example 143c (191mg, 0.5 mmol,) in dioxane (5 mL) were added Pd₂(dba)₃ (50 mg, 0.05mmol), Xantphos (30 mg, 0.05 mmol) and Cs₂CO₃ (224.5 mg, 0.75 mmol). Themixture was degassed by nitrogen for 3 times and stirred at 110° C. forovernight. When completed, the reaction was cooled to r.t., diluted withMeOH (5 mL) and filtered. The filtrate was purified directly byPrep-HPLC to give the desired product Example 143 (7.4 mg, 3.2% yield)as a off white solid. LCMS [M+1]⁺=468.2. ¹H NMR (400 MHz, DMSO-d₆) δ11.14 (s, 1H), 10.90 (s, 1H), 9.16 (s, 1H), 8.60-8.51 (m, 2H), 7.85 (s,1H), 7.76 (s, 1H), 7.67 (d, J=7.9 Hz, 1H), 7.62 (d, J=7.9 Hz, 1H), 7.34(d, J=8.0 Hz, 1H), 3.93 (s, 3H), 3.69 (s, 3H), 2.98 (s, 1H), 1.21 (s,1H), 1.09 (s, 2H), 1.04 (d, J=7.0 Hz, 2H).

Example 144

Step 1: Example 144c

A mixture of Example 144a (250 mg, 2.1 mmol), Example 144b (288 mg, 2.1mmol) and TEA (637 mg, 6.3 mmol) in 1,4-dioxane (2 mL) was stirred atroom temperature overnight. The reaction was filtered to give thedesired product Example 144c (200 mg, 76.3% yield) as a white solid. ¹HNMR (400 MHz, DMSO-d₆) δ 6.04 (s, 2H), 4.03 (t, J=8.0 Hz, 2H), 3.86 (t,J=8.0 Hz, 2H), 3.67-3.62 (m, 1H).

Step 2: Example 144

To a solution of Example 144c (66 mg, 0.53 mmol) and Example 144d (100mg, 0.27 mmol) in 1,4-dioxane (2 mL) were added Pd₂(dba)₃ (24 mg, 0.027mmol), Xantphos (31 mg, 0.053 mmol) and Cs₂CO₃ (173 mg, 0.53 mmol). Themixture was degassed by nitrogen for 3 times and stirred at 110° C.overnight. When completed, the reaction was cooled to r.t., diluted withCH₃CN (5 mL) and filtered. The filtrate was purified directly byPrep-HPLC to give the desired product Example 144 (61.3 mg, 49.7% yield)as a yellow solid. LCMS [M+1]⁺=466.2. ¹H NMR (400 MHz, DMSO-d₆) δ 10.91(s, 1H), 9.96 (s, 1H), 9.02 (s, 1H), 8.54 (s, 1H), 7.96 (s, 1H), 7.62(d, J=8.0 Hz, 1H), 7.48 (d, J=8.0 Hz, 1H), 7.25 (t, J=8.0 Hz, 1H), 4.27(t, J=8.0 Hz, 2H), 4.13 (t, J=8.0 Hz, 1H), 3.93 (s, 3H), 3.75-3.67 (m,4H).

Example 145

To a solution of Example 145a (100 mg, 0.26 mmol) and Example 145b (98mg, 0.78 mmol) in 1,4-dioxane (2 mL) were added Pd₂(dba)₃ (24 mg, 0.026mmol), Xantphos (30 mg, 0.052 mmol) and Cs₂CO₃ (170 mg, 0.52 mmol). Themixture was degassed by nitrogen for 3 times and stirred at 110° C. for2 h. When completed, the reaction was cooled to r.t., diluted with MeOH(5 mL) and filtered. The filtrate was purified directly by Prep-HPLC togive the desired product Example 145 (32 mg, 26.0% yield) as a whitesolid. LCMS [M+1]⁺=474.0. ¹H NMR (400 MHz, DMSO-d₆) δ 11.03 (s, 1H),9.92 (s, 1H), 9.08 (s, 1H), 8.54 (s, 1H), 8.05 (s, 1H), 7.71 (s, 1H),7.63 (d, J=8.0 Hz, 1H), 7.58 (d, J=8.3 Hz, 2H), 7.29 (t, J=7.9 Hz, 1H),3.93 (s, 3H), 3.69 (s, 3H), 2.94 (s, 1H), 2.23 (s, 3H), 1.05 (s, 2H),0.99 (d, J=7.6 Hz, 2H).

Example 146

Step 1: Example 146b

The solution of Example 146a (3.0 g, 19.2 mmol, 1.0 eq) in POCl₃ (30 mL)was stirred for 4 h at 100° C. After the reaction completed, it wasconcentrated under vacuo to give crude product (3.0 g, crude) which wasused to next step without further purification.

Step 2: Example 146d

To a solution of Example 146c (1.96 g, 28.4 mmol, 2.0 eq) and DIEA (14.7g, 113.6 mmol, 8.0 eq) in THF (30 mL) was added a solution of Example146b (3.0 g, crude) in DCM (20 mL) dropwise at 0° C. The reactionsolution was stirred for 30 min at r.t. The reaction solution wasdiluted with EtOAc (100 mL), washed with brine (50 mL*3), dried overNa₂SO₄ and concentrated. The residue was purified by silica gel flashcolumn chromatography, eluted with Petroleum Ether/EtOAc=(3/1) to affordthe product Example 146d (400 mg, 14% yield) as a yellow solid. LCMS[M+1]⁺=206.2.

Step 3: Example 146f

To a solution of Example 146d (400 mg, 1.94 mmol, 1.0 eq) and Example146e (402 mg, 1.94 mmol, 1.0 eq) in dry THF (15 mL) was added LiHMDS(3.88 mL, 1M in THF, 3.88 mmol, 2.0 eq) dropwise at 0° C. under N₂protection. The reaction mixture was stirred for 0.5 h at r.t. Then thesilica was added to the mixture and concentrated. The residue waspurified by silica gel flash column chromatography, eluted withDCM/MeOH=(20/1) to afford the product Example 146f (310 mg, 42% yield)as a yellow solid. LCMS [M+1]⁺=377.3.

Step 4: Example 146

To a solution of Example 146f (290 mg, 0.77 mmol, 1.0 eq) an dioxanewere added Cs₂CO₃ (502.0 mg, 1.54 mmol, 2.0 eq), Example 146g (231 mg,2.31 mmol, 3.0 eq) and BINAP (95.9 mg, 0.15 mmol, 0.2 eq) andPd₂(dba)₃CHCl₃ (82.8 mg, 0.08 mmol, 0.1 eq). The reaction mixture wasstirred for 4 h at 110° C. under N₂ protection. After cooled to roomtemperature, the solvent was removed, and the crude product was purifiedby Prep-TLC (DCM/MeOH=15/1) to afford the product Example 146 (80.5 mg,24% yield) as an off-white solid. LCMS [M+1]⁺=441.3. ¹H NMR (300 MHz,DMSO-d₆) δ 10.92 (s, 1H), 9.61 (s, 1H), 9.05 (d, J=4.8 Hz, 1H), 8.57 (s,1H), 8.03 (s, 1H), 7.64 (dd, J=7.8, 1.8 Hz, 1H), 7.52 (dd, J=8.1, 1.8Hz, 1H), 7.27 (t, J=7.8 Hz, 1H), 4.01 (t, J=7.8 Hz, 4H), 3.74 (s, 3H),2.87 (d, J=4.8 Hz, 3H), 2.23-2.08 (m, 2H).

Example 147

Step 1: 2-chloro-3-methoxyisonicotinic acid

To a solution of 2-chloro-3-methoxypyridine (50 g, 0.348 mol) in THF(500 mL) at −78° C. was added LDA (1.0 M in THF, 418 mL, 0.418 mmol)dropwise. After addition, the mixture was stirred at −78° C. for 30minutes, then dry ice was added to the reaction during 30 minutes. Thereaction was quenched with 5% w/v aqueous NaOH (200 mL) and the aqueouslayer was washed with EtOAc (200 mL×2). The organic fractions werediscarded and the pH of the aqueous layer was adjusted to 2 with a 6 Maqueous HCl solution. The aqueous layer was extracted with EtOAc (30mL×3) and the combined organic fractions dried by Na₂SO₄, filtered andconcentrated to give the desired compound as a yellow solid (35 g,53.8%).

Step 2: 2-chloro-3-methoxyisonicotinamide

To a solution of 2-chloro-3-methoxyisonicotinic acid (37 g, 0.197 mol),Boc₂O (49.84 mL, 0.217 mol) and pyridine (19.14 mL, 0.239 mol) in DCM(600 mL) at 0° C. was added NH₄HCO₃ (78.0 g, 0.985 mol). After theaddition was complete, the ice bath was removed and the reaction mixturewas allowed to warm to rt. After stirring at room temperature forovernight, the reaction mixture was concentrated on the rotovap toremove some of the DCM, and filtered to collect the liquid. The filtratewashed with H₂O (100 mL×2). The combined organic layers were washed bybrine (100 mL), dried over Na₂SO₄, filtered and concentrated underreduced pressure to afford the crude product which was purified bycolumn chromatography (DCM/MeOH=20/1) to give the title compound as abrown solid (24.0 g, Yield: 65.3%). LM-MS: m/z=187.6 [M+H]⁺

Step 3: 2-chloro-3-methoxy-4-(1H-1,2,4-triazol-3-yl)pyridine

2-chloro-3-methoxyisonicotinamide (24 g, 0.129 mol) was slurried indimethyl formamide dimethyl acetal (173 mL, 1.29 mol) and the mixturewas heated to 95° C. giving a clear, pale yellow solution. After heatingfor 1 h, the reaction was cooled and was concentrated on the rotovap andthe resulting yellow oil was azeotroped twice with 1,2-dichloroethane(40 mL portions) to ensure complete removal of any residual dimethylformamide dimethyl acetal. The crude oil thus obtained was immediatelydissolved in 50 mL of ethanol and was immediately used in the followingstep.

In a separate flask was prepared a mixture of ethanol (500 mL) andacetic acid (AcOH, 130 mL) and the resulting solution was cooled in anice bath. Once cooled, hydrazine hydrate 64 mL, 1.29 mol) was addeddropwise. At this time, the solution containing the crude dimethylformamide dimethyl acetal adduct as prepared above was transferreddropwise over 15 min by cannula into the previously preparedwell-stirred ice-cold mixture containing the hydrazine. During theaddition, a pale yellow solid formed in the solution. After the additionwas completed, the resulting cloudy yellow mixture was allowed to warmto room temperature and stirred for overnight. The reaction mixture atthis time was concentrated on the rotovap to remove some of the ethanol,diluted with additional water and filtered to collect the solid. Thesolid was washed with additional portions of water, air dried in thefunnel then under vacuum to afford 24 g (88%) of a pale yellow solid asthe desired product. LM-MS: m/z=211.6 [M+H]⁺

Step 4: 2-chloro-3-methoxy-4-(1-methyl-1H-1,2,4-triazol-3-yl)pyridine

To a solution of 2-chloro-3-methoxy-4-(1H-1,2,4-triazol-3-yl)pyridine(9.00 g, 42.7 mmol) in DMF (80 mL) was treated with potassium carbonate(17.7 g, 128.1 mmol). After cooling the resulting mixture in an icebath, a solution of iodomethane (8.1 g, 57.6 mmol) in DMF (5 mL) wasslowly added dropwise by syringe over 2 min. After the addition wascomplete, the ice bath was removed and the reaction mixture was allowedto warm to rt. After stirring at room temperature for overnight, LCMSanalysis indicated complete and clean conversion to the regioisomericmixture of products in ˜3:1 ratio, respectively. The reaction was cooledin an ice bath and was diluted with water (˜50 mL) and the solution wasextracted with EtOAc (3×40 mL) and the combined extracts were washedwith 10% aq. LiCl (2×20 mL), water (20 mL) then brine (20 mL),concentrated and purified by column chromatography (PE/EA=5/1) to affordthe title compound (5.0 g, 52%) of the major isomer as a pale yellowsolid. LM-MS: m/z=225.6 [M+H]⁺

Step 5: 3-methoxy-4-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-2-amine

To a solution of2-chloro-3-methoxy-4-(1-methyl-1H-1,2,4-triazol-3-yl)pyridine (5 g, 22.3mmol), diphenylmethanimine (6.01 g, 33.45 mmol), Sodium tert-butoxide(3.2 g, 33.45 mmol) and DPEphos (2.4 g, 4.46 mmol) in 1,4-dioxane (100mL) was added Pd₂(dba)₃ (2.0 g, 2.23 mmol). The mixture degassed by N₂for 3 times and heated to 100° C. for 1 hrs. When reaction completed,filtered, filtrate was removed in vacuo, added DCM 50 mL, 2M HCl 50 mlstirring at room temperature for 20 min, the aqueous layer was washedwith DCM (20 mL×2). the pH of the aqueous layer was adjusted to 9 with5% w/v aqueous NaOH, The aqueous layer was extracted with DCM (50 mL×6)and the combined organic fractions dried (Na₂SO₄), filtered andconcentrated and chromatography (DCM/MeOH=20/1) to give the titlecompound as a white solid, (2.6 g, 56.8%)

Step 6:6-chloro-4-((3-methoxy-4-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-2-yl)amino)-N-(methyl-d3)pyradazine-3-carboxamide

To a solution of4,6-dichloro-N-(trideuteriomethyl)pyridazine-3-carboxamide (3.97 g, 19.0mmol) and 3-methoxy-4-(1-methyl-1,2,4-triazol-3-yl)pyridin-2-amine (3.00g, 14.6 mmol) in THF (50 mL) under N₂ was added LiHMDS (1 M, 43.80 mL,43.80 mmol) at 0° C. resulting a mild exotherm. The reaction was stirredat r.t. When completed, the reaction mixture was cooled to 0° C.,quenched by adding satd. NH₄Cl (aq.), diluted with water (100 mL) andextracted by EtOAc (50 mL×3). The combined organic layers were washed bybrine (50 mL), dried over Na₂SO₄, filtered and concentrated underreduced pressure to afford the crude product which was purified bycolumn chromatography (DCM/EtOAc=3/1) to give the title compound as ayellow solid (2.70 g, 48.9%).

Step 7:6-(3-isopropyl-2-oxo-imidazolidin-1-yl)-4-[[3-methoxy-4-(1-methyl-1,2,4-triazol-3-yl)-2-pyridyl]amino]-N-(trideuteriomethyl)pyridazine-3-carboxamide

To a solution of6-chloro-4-((3-methoxy-4-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-2-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide(3.6 g, 9.5 mmol) and 1-isopropylimidazolidin-2-one (2.4 g, 19 mmol) in1,4-dioxane (30 mL) was added cesium carbonate (6.2 g, 19 mmol),Pd₂(dba)₃ (2.6 g, 2.9 mmol), and Xantphos (3.3 g, 5.7 mmol). The mixturedegassed by N₂ for 3 times and heated to 120 ° C. for 4 hrs. Whenreaction completed, filtered, filtrate was removed in vacuo,chromatography (PE/EtOAc=50/50 then DCM/MeOH=97/3) to give the desiredproduct T241 as a yellow solid (0.55 g, 12%). ¹H NMR (400 MHz, CDCl₃): δ12.20 (s, 1H), 10.16 (s, 1H), 8.28 (d, 1H), 8.22 (s, 1H), 8.14 (s, 1H),7.51 (d, 1H), 4.43-4.32 (m, 1H), 4.23 (t, 2H), 4.03 (s, 3H), 4.00 (s,3H), 3.51 (t, 2H), 1.23 (d, 6H). LM-MS: m/z=470.3 [M+H]⁺

Example 148

Step 1: Example 148b

To a solution of Example 148a (1.0 g, 5.21 mmol, 1.0 eq) in DCM (15 mL)were added CD₃NH₂.HCl (438 mg, 6.25 mmol, 1.2 eq), DIEA (3.36 g, 26.04mmol, 5.0 eq) and HATU (2.37 g, 6.25 mmol, 1.2 eq). The reaction mixturewas stirred for 4 h at r.t. The solvent was removed, and the residue waspurified by silica gel flash column chromatography, eluted with PE/EtOAc(1/1) to afford the product Example 148b (670 mg, 61.8% yield) as an offwhite solid. LCMS [M+1]⁺=208.2.

Step 2: Example 148d

To a solution of Example 148b (200 mg, 0.96 mmol, 1.0 eq) and Example148c (196 mg, 0.96 mmol, 1.0 eq) in dry THF (5 mL) was added LiHMDS(1.92 mL, 1 M in THF, 1.92 mmol, 2.0 eq) dropwise at −15° C. Thereaction solution was stirred at r.t. for 30 min. After the reaction wascompleted, the solvent was removed, the residue was purified by silicagel flash column chromatography, eluted with DCM/MeOH (20/1) to affordthe product Example 148d (212 mg, 58.7% yield) as a yellow solid. LCMS[M+1]⁺=376.3

Step 3: Example 148

To a solution of Example 148d (100 mg, 0.27 mmol, 1.0 eq) in dioxane (3mL) were added Cs₂CO₃ (260 mg, 0.80 mmol, 3.0 eq), Example 148e (102 mg,0.80 mmol, 3.0 eq) and 3^(rd) Brettphos catalyst (48 mg, 0.05 mmol, 0.2eq). The reaction mixture was stirred for 6 h at 120° C. under N₂. Themixture was filtered and the filtrate was concentrated. The crudeproduct was purified by Prep-TLC (DCM/MeOH=15/1) to afford the productExample 148 (26.1 mg, 21.0% yield) as a light yellow solid. LCMS[M+1]⁺=468.4, ¹H NMR (300 MHz, DMSO-d₆) δ 10.66 (s, 1H), 8.96 (s, 1H),8.55 (s, 1H), 8.52 (s, 1H), 8.46 (s, 1H), 7.94 (s, 1H), 7.56-7.48 (m,2H), 7.22 (t, 7.8 Hz, 1H), 3.95 (s, 3H), 3.74 (s, 3H), 3.65 (s, 4H),1.21 (s, 6H).

Example 149

Step 1: Example 149c

A solution of Example 149a (200 mg, 0.90 mmol), Example 149b (95 mg,0.91 mmol), Example 149c (26 mg, 0.18 mmol), CuI (18 mg, 0.09 mmol) andK₃PO₄ (380 mg, 1.82 mmol) in 1,4-dioxane (5 mL) was stirred at 110° C.overnight. The reaction was diluted with CH₃CN (5 mL), filtered andconcentrated to give the crude product Example 149d (210 mg, quant.) asblack oil. ¹H NMR (400 MHz, DMSO-d₆) δ 7.85 (br, 1H), 7.33 (d, J=8.0 Hz,11H), 6.43 (d, J=8.0 Hz, 1H), 5.98 (s, 2H), 4.13 (s, 2H), 3.91 (t, J=4.0Hz, 2H), 3.61 (t, J=4.0 Hz, 2H).

Step 2: Example 149

To a solution of Example 149d (210 mg, 0.90 mmol) and Example 149e (200mg, 0.52 mmol,) in 1,4-dioxane (5 mL) were added Pd₂(dba)₃ (48 mg, 0.05mmol), XantPhos (60 mg, 0.10 mmol) and Cs₂CO₃ (340 mg, 1.04 mmol). Themixture was degassed by nitrogen for 3 times and stirred at 110° C.overnight. When completed, the reaction was cooled to r.t., diluted withMeOH (5 mL) and filtered. The filtrate was purified directly byPrep-HPLC to give the desired product Example 149 (11.5 mg, 4.1% yield)as an off-white solid. LCMS [M+1]⁺=541.3. ¹H NMR (400 MHz, DMSO-d₆) δ11.05 (s, 1H), 10.08 (s, 1H), 9.09 (s, 1H), 8.54 (s, 1H), 8.20 (s, 1H),7.91 (s, 1H), 7.72-7.58 (m, 4H), 7.29 (t, J=8.0 Hz, 1H), 4.19 (s, 2H),3.96 (t, J=4.0 Hz, 2H), 3.93 (s, 3H), 3.72-3.70 (m, 5H), 2.95 (br, 1H),1.06-0.97 (m, 4H).

Example 150

Step 1: Example 150c

To a solution of Example 150a (240 mg, 2.0 mmol) in dioxane (4 mL) wereadded Example 150b (411 mg, 3.0 mmol) and TEA (606 mg, 6.0 mmol). Thereaction mixture was stirred at room temperature overnight. The mixturewas concentrated, and the residue was triturated with Petroleumether/EtOAc=1/1 (5 mL). The solid was collected by filtered and dried togive Example 150c (120 mg, 47.5% yield) as a white solid. LCMS[M+1]⁺=127.1

Step 2: Example 150

To a solution of Example 150d (100 mg, 0.27 mmol) in dioxane (3 mL) wereadded Example 150c (50 mg, 0.4 mmol), Pd₂(dba)₃ (25 mg, 0.027 mmol),Xantphos (16 mg, 0.027 mmol) and Cs₂CO₃ (176 mg, 0.26 mmol). The mixturewas sealed and heated to 120° C. for overnight. The mixture wasfiltrated and concentrated under reduced pressure. The residue waspurified by Prep-HPLC to give Example 150 (47 mg, 37.3% yield) as ayellow solid. LCMS [M+1]⁺=467.2. ¹H NMR (400 MHz, Chloroform-d) δ 10.94(s, 1H), 8.14-8.02 (m, 3H), 7.76 (d, J=7.7 Hz, 1H), 7.53 (d, J=7.2 Hz,1H), 7.26 (s, 1H), 7.14 (s, 1H), 4.15 (s, 3H), 3.99 (s, 3H), 3.81 (s,3H), 0.69 (br, 4H).

Example 151

Step 1: Example 151c

A solution of Example 151a (200 mg, 1.1 mmol) in 1,4-dioxane (35 mL)were treated with Example 151b (274 mg, 2.0 mmol) and TEA (300 mg, 3.0mmol). The mixture was stirred at r.t. for 16 h. After reactioncompleted, the solvent was concentrated, and the residue was suspendedin DCM (5 mL), and sonicated. The resulting solid was collected viafiltration, and dried to afford the desired crude product Example 151c(300 mg, crude, 190.7% yield) as a white solid.

Step 2: Example 151

To a solution of Example 151d (94 mg, 0.25 mmol) and Example 151c (150mg crude, 1.0 mmol) in dioxane (5 mL) were added Pd₂(dba)₃ (91 mg, 0.1mmol), Xantphos (59 mg, 0.1 mmol) and Cs₂CO₃ (652 mg, 2.0 mmol). Themixture was degassed by nitrogen for 3 times and stirred at 110° C. forovernight. When completed, the reaction was cooled to r.t., diluted withMeOH (5 mL) and filtered. The filtrate was purified directly byPrep-HPLC to give the desired product Example 151 (3.7 mg, 0.7% yield)as an off white solid. LCMS [M+1]⁺=484.2. ¹H NMR (400 MHz, Chloroform-d)δ 11.12 (s, 1H), 8.11 (s, 1H), 7.97-7.83 (m, 3H), 7.51-7.44 (m, 1H),4.71-4.61 (m, 2H), 4.52 (dd, J=21.4, 10.8 Hz, 2H), 4.01 (s, 3H), 3.80(s, 3H).

Example 152

To a solution of Example 152a (100 mg, 0,26 mmol,) and Example 152b (45mg, 0.41 mmol) in DMA (2.5 mL) were added Pd₂(dba)₃ (24 mg, 0.026 mmol),Xantphos (30 mg, 0.052 mmol) and Cs₂CO₃ (340 mg, 1.04 mmol). The mixturewas degassed by nitrogen for 3 times and stirred at 130° C. for 2 h.When completed, the reaction was cooled to r.t., diluted with MeOH (5mL) and filtered. The filtrate was purified directly by Prep-HPLC togive the desired product Example 152 (10.0 mg, 8.4% yield) as a whitesolid. LCMS [M+1]⁺=457.2. ¹H NMR (400 MHz, DMSO-d₆) δ 11.03 (s, 1H),10.12 (s, 1H), 9.10 (s, 1H), 8.88 (s, 1H), 8.54 (d, J=3.4 Hz, 1H), 8.08(s, 1H), 7.69 (s, 1H), 7.62 (d, J=9.3 Hz, 2H), 7.29 (t, J=7.7 Hz, 1H),3.93 (s, 3H), 3.69 (s, 3H), 2.96 (s, 1H), 2.37 (d, J=3.4 Hz, 3H), 1.06(s, 2H), 0.99 (s, 2H).

Example 153

To a solution of Example 153a (100 mg, 0.26 mmol), and Example 153b (45mg, 0.41 mmol) in DMA (2.5 mL) were added Pd₂(dba)₃ (24 mg, 0.026 mmol),Xantphos (30 mg, 0.052 mmol) and Cs₂CO₃ (340 mg, 1.04 mmol). The mixturewas degassed by nitrogen for 3 times and stirred at 130° C. for 2 h.When completed, the reaction was cooled to r.t., diluted with MeOH (5mL) and filtered. The filtrate was purified directly by Prep-HPLC togive the desired product Example 153 (20.0 mg, 17.1% yield) as a whitesolid. LCMS [M+1]⁺=457.2. ¹H NMR (400 MHz, DMSO-d₆) δ 11.07 (s, 1H),10.31 (s, 1H), 9.11 (s, 1H), 8.54 (s, 1H), 8.30 (s, 1H), 8.15 (s, 1H),7.65 (t, J=9.6 Hz, 2H), 7.29 (d, J=7.9 Hz, 1H), 7.23 (s, 1H), 3.93 (s,3H), 3.69 (s, 3H), 2.97 (s, 1H), 2.37 (s, 3H), 1.08 (s, 2H), 1.02 (s,2H).

Example 154

To a solution of Example 154a (100 mg, 0.26 mmol,) and Example 154b (45mg, 0.39 mmol) in DMA (2.5 mL) were added Pd₂(dba)₃ (24 mg, 0.026 mmol),Xantphos (30 mg, 0.052 mmol) and Cs₂CO₃ (340 mg, 1.04 mmol). The mixturewas degassed by nitrogen for 3 times and stirred at 130° C. for 2 h.When completed, the reaction was cooled to r.t., diluted with MeOH (5mL) and filtered. The filtrate was purified directly by Prep-HPLC togive the desired product Example 154 (40.0 mg, 34.2% yield) as a whitesolid. LCMS [M+1]⁺=457.2. ¹H NMR (400 MHz, DMSO-d₆) δ 11.03 (s, 1H),10.27 (s, 1H), 9.14 (s, 1H), 8.55 (s, 2H), 7.78 (s, 1H), 7.65-7.57 (m,3H), 7.30 (d, J=7.9 Hz, 1H), 3.93 (s, 3H), 3.69 (s, 3H), 2.97 (s, 1H),2.34 (s, 3H), 1.07 (s, 2H), 1.01 (s 2H).

Example 155

Step 1: Example 155c

To a solution of Example 155a (120 mg, 0.585 mmol, 1.0 eq) in DMF (10mL), was added NaH (234 mg, 60% in mineral oil, 5.85 mmol, 10.0 eq) inportions at 0° C. After Example 155b (188.8 mg, 0.878 mmol, 1.5 eq) inDMF was added to the mixture, and the reaction mixture was stirred for1.5 h at r.t. The reaction solution was poured into water (50 mL),extracted with EtOAc (50 mL*3), and the combined organic layers weredried over Na₂SO₄ and concentrated. The crude product was purified bysilica gel flash column chromatography, eluted with DCM/MeOH (20/1) toafford the product Example 155c (24 mg, 11% yield) as a yellow solid.LCMS [M+1]⁺=385.1.

Step 2: Example 155

To a solution of Example 155c (18 mg, 0.047 mmol, 1.0 eq) in dioxane (2mL) were added Cs₂CO₃ (30.1 mg, 0.094 mmol, 2.0 eq), Example 155d (10.2mg, 0.094 mmol, 2.0 eq), BINAP (5.8 mg, 0.009 mmol, 0.2 eq) andPd₂(dba)₃.CHCl₃ (4.9 mg, 0.005 mmol, 0.1eq). The reaction mixture wasstirred for 4 h at 110° C. under N₂ protection. After cooled to roomtemperature, the solvent was removed, and the crude product was purifiedby Prep-TLC (DCM/MeOH=20/1) to afford the product Example 155 (8.6 mg,41% yield) as a yellow solid. LCMS [M+1]⁺=458.3. ¹H NMR (300 MHz,DMSO-d₆) δ 12.28 (s, 1H), 10.46 (s, 1H), 9.16 (d, J=7.2 Hz, 2H), 8.66(s, 1H), 8.20-8.11 (m, 2H), 7.54-7.46 (m, 2H), 4.00 (s, 3H), 3.88 (s,3H), 3.05-2.93 (m, 1H), 2.56 (s, 3H), 1.17-0.99 m, 4H).

Example 156

Step 1: Example 156b

To a solution of Example 156a (5.0 g, 22.73 mmol, 1.0 eq) in DMF (100mL) were added K₂CO₃ (9.41 g, 68.18 mmol, 3.0 eq) and CD₃I (6.60 g,45.45 mmol, 2.0 eq) at 0° C. The reaction mixture was stirred for 16 hat r.t. The reaction was diluted with EtOAc and washed with brine. Theorganic layer dried over Na₂SO₄ and concentrated. The residue waspurified by silica gel flash column chromatography, eluted withPetroleum Ether/EtOAc (1/1) to afford the product Example 156b (1.58 g,29.3% yield) as a yellow solid. LCMS [M+1]⁺=238.2.

Step 2: Example 156c

To a solution of Example 156b (500 mg, 2.11 mmol, 1.0 eq) MeOH (10 mL)was added Pd/C (200 mg) in portions under N₂ protection, the suspensionwas degassed under vacuum and purged with H₂ three times, the reactionmixture was stirred for 30 min at r.t. under H₂ balloon. The solid wasfiltered out, the filtrate was concentrated to afford the productExample 156c (425 mg, crude, 97.3% yield) as a gray solid. LCMS[M+1]⁺=208.2.

Step 3: Example 156e

To a solution of Example 156c (425 mg, 2.05 mmol, 1.0 eq) and Example156d (429 mg, 2.05 mmol, 1.0 eq) in dry THF (15 mL) was added LiHMDS(4.11 mL, 1 M in THF, 4.11 mmol, 2.0 eq) dropwise at −15° C. Thereaction solution was stirred at −15° C. for 30 min. After the reactionwas completed, the reaction solution was concentrated. The residue waspurified by silica gel flash column chromatography, eluted withPetroleum Ether/EtOAc (1/2) to afford the product Example 156e (170 mg,27.8% yield) as a yellow solid. LCMS [M+1]⁺=380.3.

Step 4: Example 156

To a solution of Example 156e (100 mg, 0.26 mmol, 1.0 eq) in dioxane (3mL) were added Example 156f (102 mg, 0.79 mmol, 3.0 eq), Cs₂CO₃ (257 mg,0.79 mmol, 3.0 eq), BINAP (66 mg, 0.11 mmol, 0.4 eq) and Pd₂(dba)3CHCl₃(54 mg, 0.05 mmol, 0.2 eq). The reaction solution was stirred for 4 h at120° C. under N₂. The mixture was filtered and the filtrate wasconcentrated. The crude product was purified by Prep-TLC (DCM/MeOH=15/1)to give the desired product Example 156 (18.0 mg, 28.2% yield) as awhite solid. LCMS [M+1]⁺=472.3. ¹H NMR (400 MHz, DMSO-d₆) δ 10.89 (s,1H), 9.60 (s, 1H), 8.99 (s, 1H), 8.54 (s, 1H), 8.01 (s, 1H), 7.62 (d,J=8.1 Hz, 1H), 7.49 (d, J=7.8 Hz, 1H), 7.24 (t, J=8.1 Hz, 1H), 3.71 (s,2H), 3.67 (s, 2H), 1.19 (s, 6H).

Example 157

Step 1: Example 157c

A solution of Example 157a (200 mg, 1.4 mmol) in 1,4-dioxane (3 mL) weretreated with Example 157b (374 mg, 2.8 mmol) and TEA (420 mg, 4.2 mmol).The mixture was stirred at r.t. for 16 h. After reaction completed, thesolvent was concentrated, and the residue was suspended in DCM (5 mL),and sonicated. The resulting solid was collected via filtration, anddried to afford the desired product Example 157c (130 mg, 62% yield) asa white solid. LCMS [M+1]⁺=151.0

Step 2: Example 157

To a solution of Example 157d (157 mg, 0.42 mmol) and Example 157c (300mg, 2.1 mmol) in dioxane (5 mL) were added Pd₂(dba)₃ (91 mg, 0.1 mmol),Xantphos (59 mg, 0.1 mmol) and Cs₂CO₃ (325.8 mg, 1.0 mmol). The mixturewas degassed by nitrogen for 3 times and stirred at 110° C. forovernight. When completed, the reaction was cooled to r.t., diluted withMeOH (5 mL) and filtered. The filtrate was purified directly byPrep-HPLC to give the desired product Example 157 (14.8 mg, 7.2% yield)as a off white solid. LCMS [M+1]⁺=491.2. ¹H NMR (400 MHz, DMSO-d₆) δ10.90 (s, 1H), 9.84 (s, 1H), 9.01 (s, 1H), 8.54 (s, 1H), 7.98 (s, 1H),7.62 (d, J=7.7 Hz, 1H), 7.48 (d, J=7.8 Hz, 1H), 7.26 (d, J=8.1 Hz, 1H),6.16-6.44 (t, 1H), 4.09 (s, 2H) 3.93 (s, 5H), 3.71 (s, 3H), 3.06 (s,1H).

Example 158

Step 1: Example 158c

To a solution of Example 158a (200 mg, 2.29 mmol) in dioxane (5 mL) wereadded Example 158b (400 mg, 2.91 mmol), and TEA (795 mg, 7.87 mmol). Thereaction mixture was stirred at room temperature overnight. Then themixture was diluted with EtOAc, washed by water, brine, and dried overanhydrous Na₂SO₄. The solution was concentrated to afford crude Example158c (170 mg, 57.2% yield) and used directly for next step.

Step 2: Example 158

To a solution of Example 158d (100 mg, 0.26 mmol) and Example 158c (120mg, 0.92 mmol) in DMA (2.5 mL) were added Pd₂(dba)₃ (24 mg, 0.026 mmol),Xantphos (30 mg, 0.052 mmol) and Cs₂CO₃ (340 mg, 1.04 mmol). The mixturewas degassed by nitrogen for 3 times and stirred at 130° C. for 2 h.When completed, the reaction was cooled to r.t., diluted with MeOH (5mL) and filtered. The filtrate was purified directly by Prep-HPLC togive the desired product Example 158 (14.0 mg, 13.1% yield) as a whitesolid. LCMS [M+1]⁺=471.3. ¹H NMR (400 MHz, DMSO-d₆) δ 10.90 (s, 1H),9.74 (s, 1H), 9.01 (s, 8.54 (s, 1H), 7.99 (s, 1H), 7.62 (d, J=7.6 Hz,1H), 7.49 (d, J=7.9 Hz, 1H), 7.25 (d, J=8.1 Hz, 1H), 4.16 (d, J=11.1 Hz,4H), 3.93 (s, 3H), 3.79 (s, 2H), 3.71 (s, 3H), 3.18 (s, 3H).

Example 159

Step 1: Example 159c

To a solution of Example 159a (1.0 g, 4.2 mmol, 1.0 eq) in dioxane (15mL) were added Cs₂CO₃ (2.7 g, 8.4 mmol, 2.0 eq), Example 159b (861.8 mg,5.04 mmol, 1.2 eq), BINAP (523.3 mg, 0.84 mmol, 0.2 eq) andPd₂(dba)₃.CHCl₃ (434.7 mg, 0.42 mmol, 0.1 eq). The reaction mixture wasstirred for 4 h at 110° C. under N₂ protection. After cooled to roomtemperature, the solvent was removed. The crude product was purified bysilica gel flash column chromatography (DCM/MeOH=20/1) to afford theproduct Example 159c (1.0 g, 67% yield) as a yellow solid. LCMS=369.3.

Step 2: Example 159e

To a solution of Example 159c (1.0 g, 2.7 mmol, 1.0 eq) in THF (10 mL)was added Example 159d (40.5 mL, 1.0 M in THF, 40.5 mmol, 15.0 eq)dropwise at 0° C. under N₂ protection. The mixture was stirred for 0.5 hat r.t. The reaction was poured into saturated aqueous of NH₄Cl (70 mL)and extracted with EtOAc (100 mL*3). The combined organic layer waswashed with brine, dried over Na₂SO₄, and concentrated. The crudeproduct was purified by silica gel flash column chromatography(DCM/MeOH=20/1) to afford the product Example 159e (640 mg, 68% yield)as a yellow solid. LCMS [M+1]⁺=350.2.

Step 3: Example 159

To a solution of Example 159e (300 mg, 0.86 mmol, 1.0 eq) in dioxane (5mL) were added Cs₂CO₃ (560 mg, 1.72 mmol, 2.0 eq), Example 159f (176 mg,1.0 mmol, 1.2 eq), BINAP (107.2 mg, 0.172 mmol, 0.2 eq) andPd₂(dba)₃.CHCl₃(89 mg, 0.086 mmol, 0.1 eq). The reaction mixture wasstirred for 4 h at 110° C. under N₂ protection. After cooled to roomtemperature, the solvent was removed. The crude product was purified bysilica gel flash column chromatography (DCM/MeOH=20/1) to give 270 mgcrude product (90% purity) and further purified by Prep-TLC(DCM/MeOH=20/1) to afford the product Example 159 (120 mg, 32% yield) asan off-white solid. LCMS [M+1]⁺=486.4. ¹H NMR (300 MHz, DMSO-d₆) δ 11.89(s, 1H), 10.28 (s, 1H), 9.17 (s, 1H), 9.02 (s, 1H), 8.64 (dd, J=4.8, 1.8Hz, 1H), 8.27 (dd, J=7.8, 1.8 Hz, 1H), 7.99 (dd, J=10.8, 8.41 Hz, 1H),7.58 (dd, J=8.1, 2.1 Hz, 1H), 7.34 (dd, J=7.8, 4.8 Hz, 1H), 5.28 (s,1H), 3.30 (s, 3H), 3.01-2.86 (m, 1H), 1.49 (s, 6H), 1.14-0.97 (m, 4H).

Example 160

Step 1:2-chloro-3-methoxy-4-[1-(trideuteriomethyl)-1,2,4-triazol-3-yl]pyridine

To a solution of 2-chloro-3-methoxy-4-(1H-1,2,4-triazol-3-yl)pyridine(10.00 g, 17.5 mmol) in DMF (50 mL) was treated with potassium carbonate(13.1 g, 95.0 mmol). a solution of trideuterioiodomethane (8.26 g, 57.0mmol) in DMF (5 mL) was slowly added dropwise by syringe over 2 min. Thereaction was stirring at room temperature for 4 h, The reaction wascooled in an ice bath and was diluted with water (50 mL) and thesolution was extracted with EtOAc (3×50 mL) and the combined extractswere washed water (50 mL) then brine (50 mL), dried over Na₂SO₄,filtered and concentrated under reduced pressure to afford the crudeproduct which was purified by column chromatography (PE/EtOAc=3/1) togive the title compound as a yellow solid (8.0 g, 74%).

Step 2:3-methoxy-4-[1-(trideuteriomethyl)-1,2,4-triazol-3-yl]pyridin-2-amine

To a solution of2-chloro-3-methoxy-4-(1-methyl-1H-1,2,4-triazol-3-yl)pyridine (8.0 g,35.1 mmol), diphenylmethanimine (7.64 g, 42.2 mmol), Sodiumtert-butoxide (6.75 g, 70.3 mmol) and DPEphos (1.88 g, 3.51 mmol) in1,4-dioxane (100 mL) was added Pd₂(dba)₃ (3.22 g, 3.51 mmol). Themixture degassed by N₂ for 3 times and heated to 100° C. for 1 hr. Whenthe reaction completed, filtered, filtrate was removed in vacuo, AddedDCM 50 mL, 2N HCl 50 mL stirring at room temperature for 20 min, theaqueous layer was washed with DCM (20 mL×2). the pH of the aqueous layerwas adjusted to 9 with 5% w/v aqueous NaOH, The aqueous layer wasextracted with DCM (50 mL×6) and the combined organic fractions dried(Na₂SO₄), filtered and concentrated and chromatography (DCM/MeOH=20/1)to give the title compound as a white solid. (3.2 g, 43.7%)

Step 3:6-chloro-4-[[3-methoxy-4-(1-methyl-1,2,4-triazol-3-yl)-2-pyridyl]amino]-N-(trideuteriomethyl)pyridazine-3-carboxamide

To a solution of4,6-dichloro-N-(trideuteriomethyl)pyridazine-3-carboxamide (4.18 g, 20.0mmol) and3-methoxy-4-[1-(trideuteriomethyl)-1,2,4-triazol-3-yl]pyridin-2-amine(3.20 g, 15.4 mmol) in THF (50 mL) under N₂ was added LiHMDS (1 M, 46.2mL, 46.2 mmol) at 0° C. resulting a mild exotherm. The reaction wasstirred at r.t. When completed, The reaction mixture was cooled to 0°C., quenched by adding satd. NH₄Cl (aq.), diluted with water (100 mL)and extracted by EtOAc (50 mL×3). The combined organic layers werewashed by brine (50 mL), dried over Na₂SO₄, filtered and concentratedunder reduced pressure to afford the crude product which was purified bycolumn chromatography (DCM/EtOAc=3/1) to give the title compound as ayellow solid (2.70 g, 46.1%).

Step 4:6-(3-isopropyl-2-oxo-imidazolidin-1-yl)-4-[[3-methoxy-4-[1-(trideuteriomethyl)-1,2,4-triazol-3-yl]-2-pyridyl]amino]-N-(trideuteriomethyl)pyridazine-3-carboxamide

To a solution of6-chloro-4-[[3-methoxy--4-(1-methyl-1,2,4-triazol-3-yl)-2-pyridyl]amino]-N-(trideuteriomethyl)pyridazine-3-carboxamide(2.8 g, 7.4 mmol) and 1-isopropylimidazolidin-2-one (1.9 g, 15 mmol)1,4-dioxane (30 mL) was added cesium carbonate (4.8 g, 15 mmol),Pd₂(dba)₃ (2.0 g, 2.2 mmol), and Xantphos (2.6 g, 4.4 mmol).The mixturedegassed by N₂ for 3 times and heated to 120° C. for 4 hrs. Whenreaction completed, filtered, filtrate was removed in vacuo,chromatography (PE/EtOAc=50/50 then DCM/MeOH=97/3) to give the desiredproduct T 311 as a yellow solid (0.58 g, 17%). ¹H NMR (400 MHz, CDCl₃) δ12.20 (s, 1H), 10.16 (s, 1H), 8.28 (d, 1H), 8.22 (s, 1H), 8.14 (s, 1H),7.51 (d, 1H), 4.43-4.32 (m, 1H), 4.23 (t, 2H), 4.00 (s, 3H), 3.51 (t,2H), 1.23 (d, 6H). LM-MS: m/z=473.3 [M+H]⁺

Example 161

Step 1: Example 161b

To a solution of Example 161a (383 mg, 1.0 mmol,) in dioxane (10 mL)were added NH₂Boc (176 mg, 1.5 mmol), Pd₂(dba)₃ (91 mg, 0.1 mmol),Xantphos (60 mg, 0.1 mmol) and Cs₂CO₃ (652 mg, 2.0 mmol). The mixturewas sealed and heated to 100° C. for 8 h. The mixture was cooled to roomtemperature, diluted by EtOAc, washed by water, dried over anhydrousNa₂SO₄, and then concentrated under reduced pressure. The residue waspurified by silica gel flash column chromatography, eluted with DCM/MeOH(10/1) to afford the product Example 161b (401 mg, 86.4% yield) as ayellow solid. LCMS [M+1]⁺=465.2.

Step 2: Example 161c

A solution of Example 169b (401 mg, 0.86 mmol) in HCl/EtOAc (2 mL) wasstirred at room temperature for 3 h. Then the mixture was concentrated,and used at next step directly.

Step 3: Example 161

To a solution of Example 161c (40 mg, 0.1 mmol) and Example 161d (10.4mg, 0.1 mmol) in pyridine (3 mL) was added POCl₃ (77 mg, 0.5 mmol) at 0°C. The reaction mixture was stirred at 0° C. for 10 min. Then water (5mL) was added dropwise, and the mixture was extracted with DCM (6 mL).The organic phase was dried over anhydrous Na₂SO₄, concentrated underreduced pressure. The residue was purified by Prep-HPLC to give Example161 (12.1 mg, 26.9% yield) as a white solid. LCMS [M+1]⁺=451.2. ¹H NMR(400 MHz, DMSO-d₆) δ 11.01 (s, 1H), 10.95 (s, 1H), 9.11 (s, 1H), 8.53(s, 1H), 8.00 (s, 1H), 7.63 (d, J=7.8 Hz, 1H), 7.51 (d, J=7.8 Hz, 1H),7.25 (t, J=7.9 Hz, 1H), 4.97 (s, 1H), 4.80 (s, 1H), 3.92 (s, 3H), 3.67(s, 3H), 2.98 (s, 1H), 2.19 (s, 1H), 1.58 (d, J=23.5 Hz, 1H), 1.21 (s,2H), 1.10-1.00 (m, 4H).

Example 162

Step 1: Example 162c

A solution of Example 162a (800 mg, 17.34 mmol) in 1,4-dioxane (35 mL)was treated with Example 162b (1.0 g, 7.34 mmol) and Na₂CO₃ (1.2 g, 11.1mmol). The mixture was stirred at r.t. for 16 h. After reactioncompleted, the solvent was concentrated, the residue was suspended inDCM (5 mL), sonicated and the resulting solid was collected viafiltration, dried to afford the desired product Example 162c (300 mg,35.3% yield) as a white solid.

Step 2: Example 162

To a solution of Example 162d (58 mg, 0.5 mmol) and Example 162c (94 mg,0.25 mmol) in dioxane (3 mL) were added Pd₂(dba)₃ (46 mg, 0.05 mmol),Xantphos (30 mg, 0.05 mmol) and Cs₂CO₃ (163 mg, 0.5 mmol). The mixturewas degassed by nitrogen for 3 times and stirred at 110° C. forovernight. When completed, the reaction was cooled to r.t., diluted withMeOH (5 mL) and filtered. The filtrate was purified directly byPrep-HPLC to give the desired product Example 162 (2.7 mg, yield: 11.8%)as a off white solid. LCMS [M+1]⁺=457.2. ¹H NMR (400 MHz, DMSO-d₆) δ10.90 (s, 1H), 9.67 (s, 1H), 9.00 (s, 1H), 8.54 (s, 1H), 8.00 (s, 1H),7.62 (d, J=7.6 Hz, 1H), 7.49 (d, J=7.8 Hz, 1H), 7.25 (d, J=8.4 Hz, 1H),5.62 (d, J=6.2 Hz, 1H), 4.38 (s, 1H), 4.17 (s, 2H), 3.93 (s, 3H),3.76-3.69 (m, 5H),

Example 163

Step 1: Example 163c

To a solution of Example 163a (7.5 g, 43.0 mmol, 1.0 eq) in THF (100 mL)was added Example 163b (21.4 mL, 3.0 M in THF, 64.2 mmol, 1.5 eq)dropwise at −20′C under N₂ protection. The mixture was stirred at r.t.for 0.5 h. The reaction was quenched with saturated aqueous of NH₄Cl (80mL) and extracted with EtOAc (150 mL*2). The combined organic layerswere washed with brine, dried over Na₂SO₄and concentrated. The residuewas purified by silica gel flash column chromatography (PetroleumEther/EtOAc=5/1) to afford the product Example 163c (4.0 g, 45.8% yield)as yellow oil. LCMS [M+1]⁺=206.1.

Step 2: Example 163d

To a solution of Example 163c (3.8 g, 18.0 mmol, 1.0 eq) in DCM (100 mL)was added MnO₂ (40.1 g, 450 mmol, 25.0 eq), and the reaction mixture wasstirred at r.t. for 16 h. The reaction mixture was filtered and thefiltrate was concentrated. The crude product was purified by silica gelflash column chromatography (Petroleum Ether/EtOAc=10/1) to afford theproduct Example 163d (2.5 g. 66.5% yield) as an off-white solid. LCMS[M+1]⁺=204.1.

Step 3: Example 163f

To a solution of Example 163d (100 mg, 0.49 mmol, 1.0 eq) dioxane (2.0mL) were added Cs₂CO₃ (320 mg, 0.98 mmol, 2.0 eq), Example 163e (41.9mg, 0.49 mmol, 1.0 eq). BINAP (61.3 mg, 0.098 mmol, 0.2 eq) andPd₂(dba)₃.CHCl₃ (50.9 mg, 0.049 mmol, 0.1 eq). The reaction mixture wasstirred for 2 h at 80° C. under N₂ protection. After cooling to r.t.,the solvent was concentrated under vacuum. The residue was purified bysilica gel flash column chromatography (Petroleum Ether/EtOAc=3/1) toafford the product Example 163f (60 mg, 48.4% yield) as a yellow solid.LCMS [M+1]⁺=253.2.

Step 4: Example 163i

To a solution of Example 163g (28.0 g, 243.4 mmol, 1.0 eq) in MeOH (400mL) at 0° C. (ice-water bath) was added Example 163h (16.0 g, 267.7mmol, 1.1 eq) dropwise. After addition, the reaction was stirred at r.t.for 16 h. The solution was concentrated in vacuum and then swapped withTHF (80 mL*4) to remove the MeOH residue. After removal of solvent byevaporation, Example 163i (15.0 g, 83.8% yield) was obtained as yellowoil.

Step 5: Example 163k

To a solution of Example 163j (40.0 g, 279.7 mmol, 1.0 eq) in dry THF(400 mL) was added LDA (181.8 mL, 2 M in THF, 363.6 mmol, 1.3 eq) at−70° C. dropwise, which was stirred for additional 40 min at the sametemperature after addition. I₂ (92.3 g, 363.6 mmol, 1.3 eq) in THF (100mL) was added to the solution dropwise. After addition, the reaction waswarmed to r.t. and stirred for 2 h. The mixture was quenched withsaturated aqueous of NH₄Cl (200 mL), extracted with EtOAc (200 mL*3).The combined organic layers were washed with brine, dried over Na₂SO₄and concentrated in vacuum. The residue was purified by silica gel flashcolumn chromatography (Petroleum Ether/EtOAc=80/1) to afford the desiredproduct Example 163k (20.0 g, 26.6% yield) as a white solid. LCMS[M+1]⁺=270.1

Step 6: Example 163l

To a solution of Example 163k (15.0 g, 55.6 mmol, 1.0 eq) in NMP (50 mL)was added CuCN (9.9 g, 111.2 mmol, 2.0 eq), and the mixture was stirredfor 5 h at 120° C. After cooling to room temperature, the mixture wasdiluted with EtOAc (200 mL) and filtered. The filtrate was washed withbrine (50 mL*3), dried over Na₂SO₄ and concentrated in vacuum. Theresidue was purified by silica gel flash column chromatography(Petroleum Ether/EtOAc=50/1) to afford the desired product Example 163l(7.5 g, 80.1% yield) as a yellow solid. LCMS [M+1]⁺=169.2.

Step 7: Example 163m

To a solution of Example 163l (5.0 g, 29.8 mmol, 1.0 eq) and Example163i (4.4 g, 59.6 mmol, 2.0 eq) in THF (150 mL) was added t-BuOK (7.3 g,65.6 mmol, 2.2 eq) in portions at 0° C. After addition, the mixture waswarmed to r.t. and stirred for 5 h. The mixture was concentrated invacuum. The residue was purified by silica gel flash columnchromatography (Petroleum Ether/EtOAc=1/1) to afford the product Example163m (2.6 g, 42.7% yield) as a white solid. LCMS [M+1]⁺=225.2.

Step 8: Example 163o

To a solution of Example 163m (1.1 g, 4.9 mmol, 1.0 eq) in dioxane (20mL) were added Cs₂CO₃ (3.26 g, 9.8 mmol, 2.0 eq), Example 163n (1.37 g,5.39 mmol, 1.1 eq), BINAP (62.3 mg, 0.98 mmol, 0.2 eq) andPd₂(dba)₃.CHCl₃ (517 mg, 0.49 mmol, 0.1 eq). The reaction mixture wasstirred for 3 h at 90° C. under N₂ protection. After the reaction wascompleted, the solvent was removed, and the residue was purified bysilica gel flash column chromatography (DCM/MeOH=20/1) to afford theproduct Example 163o (1.4 g, 89.3% yield) as a yellow solid. LCMS[M+1]⁺=326.3.

Step 9: Example 163p

A solution of Example 163o (1.4 g, 4.29 mmol, 1.0 eq) in TFA (20 mL) wasstirred for 1 h at 70° C. After the reaction was completed, it wasconcentrated in vacuum. The residue was dissolved in MeOH (20 mL) andbasified with NaHCO₃ (910 mg, 8.58 mmol, 2.0 eq). The solid was filteredout, and the filtrate was concentrated in vacuum, The residue waspurified by silica gel flash column chromatography (DCM/MeOH=20/1) toafford the product Example 163p (750 mg, 84.9% yield) as a light graysolid. [M+1]⁺=206.2.

Step 10: Example 163

To a solution of Example 163f (22 mg, 0.11 mmol, 1.0 eq) and Example163p (30 mg, 0.12 mmol, 0.9 eq) in dioxane (2 mL) were added Cs₂CO₃(77.3 mg, 0.22 mmol, 2.0 eq), Pd₂(dba)₃. CHCl₃ (12.3 mg, 0.011 mmol, 0.1eq) and BINAP (15.0 mg, 0.022 mmol, 0.2 eq). The reaction mixture wasstirred for 3 h at 110° C. under N₂ protection. The reaction solutionwas filtered and the filtrate was concentrated in vacuo. The crudeproduct was purified by Prep-TLC (DCM/MeOH=30/1) to afford the desiredproduct Example 163 (13.8 mg, 27.6% yield) as a light yellow solid. LCMS[M+1]⁺=422.3. ¹H NMR (300 MHz, DMSO-d₆) δ 12.36 (s, 1H), 10.91 (s, 1H),9.71 (s, 1H), 8.96 (s, 1H), 8.67 (s, 1H), 8.14 (d, 5.4 Hz, 1H), 7.50 (d,J=5.1 Hz, 1H), 4.00 (s, 3H), 3.92 (s, 3H), 3.16 (q, J=7.2 Hz, 2H),2.12-2.04 (m, 1H), 1.15 (t, J=7.2 Hz, 3H), 0.89-0.82 (m, 4H).

Example 164

Step 1: 2-methylazetidine-1-carboxamide

To a solution of 2-methylazetidine hydrochloride (120 mg, 1.12 mmol),phenyl carbamate (184 mg, 1.34 mmol) 1,4-dioxane (20 mL) was added NEt₃(0.5 mL, 3.36 mmol) and stirred at r.t. for 16 hrs. After reactioncompleted, the solvent was concentrated, the residue was suspended inDCM (5 mL), sonicated and the resulting solid was collected viafiltration, dried to afford the desired product (150 mg, 89%) as a whitesolid. LM-MS: m/z=115.1 [M+H]⁺

Step 24-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)-6-(2-methylazetidine-1-carboxamido)pyridazine-3-carboxamide

To a solution of6-chloro-4-((2-methoxy-3-(1-3ethyl-1H-1,2,4-triazol-3-yl)

phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (244.7 mg, 0.65mmol) and 2-methylazetidine-1-carboxamide (150 mg, 1.0 mmol) in1,4-dioxane (10 mL) was added Pd₂(dba)3 (60 mg, 0.065 mmol), XantPhos(75 mg, 0.13 mmol) and Cs₂CO₃ (635 mg, 1.95 mmol). The mixture wassealed, degassed by nitrogen for 3 times and stirred at 120° C. for 4hrs. When completed, the reaction was cooled to r.t. and filtered. Thefiltrate was purified directly by prep-HPLC to give the racemic product(125 mg, yield: 42%) as a white solid. LM-MS: m/z=455.3 [M+H]⁺

The racemic compound was separated by SFC, and got enantiomer A (49.5mg, R.T.: 3.008 min). ¹H NMR (400 MHz, CDCl₃) δ 11.19 (s, 1H), 8.15 (s,1H), 8.10 (s, 1H), 7.93 (s, 1H), 7.82 (dd, 1H), 7.53 (dd, 1H), 7.31-7.24(m. 2H), 4.53 (dd, 1H), 4.17-4.01 (m, 2H), 4.00 (s, 3H), 3.82 (s, 3H),2.53-2.36 (m, 1H), 1.98-1.83 (m, 1H), 1.50 (d, 3H). ee %=100% ; LM-MS:m/z=455.3 [M+H]⁺

enantiomer B (49.9 mg, R.T.: 4.240 min). ¹H NMR (400 MHz, CDCl₃) δ 11.13(s, 1H), 8.13 (s, 1H), 8.09 (s, 1H), 7.96 (s, 1H), 7.80 (dd, 1H), 7.53(d, 1H), 7.32-7.21 (m, 2H), 4.52 (dd, 1H), 4.14-4.02 (m, 2H), 4.00 (s,3H), 3.82 (s, 3H), 2.57-2.35 (m, 1H), 2.05-1.81 (m, 1H), 1.50 (d, 3H).ee %=100%; LM-MS: m/z=455.3 [M+H]⁺

Example 165

Step 1: Example 165c

To a solution of Example 165a (270 mg, 3.1 mmol) in dioxane (5 mL) wereadded Example 165b (500 mg, 3.64 mmol), and TEA (795 mg, 7.87 mmol). Thereaction mixture was stirred at room temperature overnight. Then themixture was diluted with EtOAc, washed by water, brine, and dried overanhydrous Na₂SO₄. The solution was concentrated to afford crude Example165c (200 mg, 49.6% yield) and used directly for next step.

Step 2: Example 165

To a solution of Example 165d (100 mg, 0.26 mmol) and Example 165c (120mg, 0.92 mmol) in DMA (2.5 mL) were added Pd₂(dba)₃ (24 mg, 0.026 mmol),xantphos (30 mg, 0.052 mmol) and Cs₂CO₃ (340 mg, 1.04 mmol). The mixturewas degassed by nitrogen for 3 times and stirred at 130° C. for 2 h.When completed, the reaction was cooled to r.t., diluted with MeOH (5mL) and filtered. The filtrate was purified directly by Prep-HPLC togive the desired product Example 165 (46.0 mg, 37.6% yield) as a whitesolid. LCMS [M+1]⁺=471.50. ¹H NMR (400 MHz, DMSO-d₆) δ 10.89 (s, 1H),9.67 (s, 1H), 8.99 (s, 1H), 8.54 (s, 1H), 8.01 (s, 1H), 7.62 (d, J=7.9Hz, 1H), 7.48 (d, J=7.9 Hz, 1H), 7.24 (s, 1H), 5.54 (s, 1H), 3.93 (s,3H), 3.83 (br, 4H), 3.71 (s, 3H), 1.33 (s, 3H).

Example 166

Step 1: Example 166c

To a solution of Example 166a (2.0 g, 8.0 mmol, 1.0 eq) in dioxane (20mL) were added Cs₂CO₃ (5.2 g, 16 mmol, 2.0 eq), Example 166b (1.36 g, 16mmol, 2.0 eq), BINAP (997 mg, 1.6 mmol, 0.2 eq) and Pd₂(dba)₃.CHCl₃ (800mg, 0.8 mmol, 0.1 eq). The reaction mixture was stirred for 2 h at 110°C. under N₂ protection. After cooled to room temperature, the solventwas removed. The crude product was purified by silica gel flash columnchromatography (Petroleum Ether/EtOAc=1/1) to afford the product Example166c (1.9 g, 86% yield) as yellow oil. LCMS [M+1]⁺=284.2.

Step 2: Example 166e

To a solution of Example 166c (1.9 g, 7.0 mmol, 1.0 eq) in THF (20 mL)was added Example 166d (210 mL, 1.0 M in THF, 210 mmol, 30.0 eq)dropwise at 0° C. under N₂ protection. The mixture was stirred for 0.5 hat r.t. The reaction was poured into saturated aqueous of NH₄Cl (200 mL)and extracted with EtOAc (150 mL*3). The combined organic layer werewashed with brine, dried over Na₂SO₄and concentrated. The crude productwas purified by silica gel flash column chromatography (PetroleumEther/EtOAc=2/1) to afford the product Example 166e (850 mg, 47% yield)as a yellow solid. LCMS [M+1]⁺=265.2.

Step 3: Example 166

To a solution of Example 166e (650 mg, 2.33 mmol, 1.2 eq) in dioxane (10mL) were added Cs₂CO₃ (1.3 g, 3.88 mmol, 2.0 eq), Example 166f (400 mg,1.94 mmol, 1.0 eq), BINAP (241.7 mg, 0.388 mmol, 0.2 eq) andPd₂(dba)₃.CHCl₃ (200.8 mg, 0.194 mmol, 0.1 eq). The reaction mixture wasstirred for 4 h at 110° C. under N₂ protection. After cooled to roomtemperature, the solvent was removed. The crude product was purified bysilica gel flash column chromatography (DCM/MeOH=20/1) to obtained 580mg crude product (90% purity), which was further purified by Prep-HPLC(Prep-C18, 5 μM XBridge column, 19×150 mm, Waters; gradient elution of35% MeCN in water to 55% MeCN in water over a 7 min period, where theaqueous phase contains 10 mM NH₄HCO₃+0.5% ammonia) to afford the productExample 166 (401.4 mg, 48% yield) as a white solid. LCMS [M+1]⁺=434.4.¹H NMR (300 MHz, DMSO-d₆) δ 12.30 (s, 1H), 10.94 (s, 1H), 9.70 (s, 1H),9.21 (s, 1H), 8.66 (s, 1H), 8.13 (d, J=5.1 Hz, 1H), 7.49 (d, J=5.1 Hz,1H), 3.99 (s, 3H), 3.86 (s, 3H), 3.11-2.96 (m, 1H), 2.15-2.04 (m, 1H),1.19-1.03 (m, 4H), 0.92-0.80 (m, 4H).

Example 169

Step 1: Example 169c

To a solution of Example 169a (123 mg, 1.0 mmol) and Example 169b (206mg, 1.5 mmol) in dioxane (3 mL) was added Na₂CO₃ (212 mg, 2.0 mmol). Thereaction mixture was stirred at r.t. overnight. The mixture wasfiltrated, the solid was washed by DCM, and the combined filtrate wasused directly at next step.

Step 2: Example 169d

To a solution of Example 169c was added imidazole (350 mg, 5.0 mmol) inportions, followed by addition of TBSCl (300 mg, 2.0 mmol). The reactionmixture was stirred at room temperature overnight. The mixture wasconcentrated, and the crude product was purified by silica gel flashcolumn chromatography, eluted with (DCM/MeOH=30/1) to afford the productExample 169d (60 mg, 24.5% yield) as a white solid.

Step 3: Example 169f

To a solution of Example 169d (60 mg, 0.26 mmol) in dioxane (5 mL) wereadded Example 169e (100 mg, 0.26 mmol), Pd₂(dba)₃ (24 mg, 0.027 mmol),Xantphos (16 mg, 0.027 mmol) and Cs₂CO₃ (130 mg, 0.40 mmol). The mixturewas sealed and heated to 110° C. for overnight. The mixture wasfiltrated and concentrated under reduced pressure to give crude Example169f (190 mg, quant.).

Step 4: Example 169

To a solution of Example 169f (130 mg, crude, 0.22 mmol) in DCM (4 mL)was added TFA (1 mL). The mixture was stirred at r.t. for 30 min. Themixture was concentrated under reduced pressure, and the residue waspurified by Prep-H.PLC (Prep-C18, 5 μM XBridge column, 19×150 min,Waters; gradient elution of 35% MeCN in water to 55% MeCN in water overa 7 min period, where the aqueous phase contains 10 mM NH₄HCO₃+0.5%ammonia) to give Example 169 (2 mg, 1.9% yield over 2 steps) as a whitesolid. LCMS [M+1]⁺=471.2. ¹H NMR (300 MHz, CDCl₃) δ 10.94 (s, 1H),8.11-8.03 (m, 3H), 7.77 (d, J=8.0 Hz, 1H), 7.51 (d, J=8.0 Hz, 1H), 4.14(br, 2H), 4.00 (s, 3H), 3.90 (s, 2H), 3.80 (s, 5H), 2.83 (br, 1H), 1.25(s, 1H).

Example 171

Step 1: Example 171c

To a solution of Example 171a (5.0 g, 26.3 mmol, 1.0 eq) in Example 171b(50 mL) was added NaH (3.15 g, 60% in mineral oil, 78.9 mmol, 3.0 eq) inportions at 0° C. The reaction mixture was stirred at r.t. for 3 h. Thereaction mixture was diluted with EtOAc (100 mL), quenched with 2 Naqueous HCl (15 mL), washed with brine (50 mL), dried over Na₂SO₄ andconcentrated. The crude product was purified by silica gel flash columnchromatography (Petroleum Ether/EtOAc=3/1) to give the desired productExample 171c (4.1 g, 64.0% yield) as a light yellow solid, LCMS[M+1]⁺=244.2.

Step 2: Example 171d

To a solution of Example 171c (4.1 g, 16.80 mmol, 1.0 eq) and K₂CO₃(2.55 g, 18.48 mmol, 1.1 eq) in DMF (50 mL) was added CD₃I (2.68 g,18.48 mmol, 1.1 eq) at 0° C. The reaction mixture was stirred at r.t.for 6 h. The mixture was diluted with EtOAc (100 mL) and washed withbrine (50 mL*3). The organic layer was dried by Na₂SO₄ and concentrated.The crude product was purified by silica gel flash columnchromatography(Petroleum ether/EtOAc=3/1) to give the desired productExample 171d (2.83 g, 64.5% yield) as colorless oil. LCMS [M+1]⁺=261.1.

Step 3: Example 171e

To a solution of Example 171d (2.83 g, 10.84 mmol, 1.0 eq) in AcOH (20mL) was added conc. HCl (40 mL). The reaction solution was heated at100° C. for 16 h. After cooled to r.t., the mixture was concentrated,diluted with H₂O (20 mL) and extracted with EtOAc (30 mL*3). Thecombined organic layer was washed with brine (50 mL), dried by Na₂SO₄andconcentrated. The crude product was purified by silica gel flash columnchromatography (Petroleum ether/EtOAc=3/1) to give the desired productExample 171e (1.12 g, 54.7% yield) as a white solid. LCMS [M+1]⁺=189.2.

Step 4: Example 171f

To a solution of Example 171e (1.12 g, 5.94 mmol, 1.0 eq) in CH₃CN (15mL) was added POCl₃ (2 mL). The reaction solution was heated at 85° C.for 1 h. After cooled to r.t., the mixture was concentrated and dilutedwith EtOAc (5 mL). The solution was added to a mixed solution of EtOAc(20 mL) and saturated aqueous NaHCO₃ (20 mL). After separation, theaqueous layer was extracted with EtOAc (20 mL*3). The combined organiclayer was washed with brine (20 mL), dried by Na₂SO₄ and concentrated.The crude product was purified by silica gel flash column chromatography(Petroleum ether/EtOAc=8/1) to give the desired product Example 171f(1.05 g, 85.4% yield) as a white solid. LCMS [M+1]⁺=207.1.

Step 5: Example 171k

To a solution of Example 171f (100 mg, 0.48 mmol, 1.0 eq) in dioxane (4mL) were added Example 171g (37 mg, 0.43 mmol, 0.9 eq), Cs₂CO₃ (315 mg,0.97 mmol, 2.0 eq), BINAP (30 mg, 0.048 mmol, 0.1 eq) andPd₂(dba)₃.CHCl₃ (50 mg, 0.048 mmol, 0.1 eq). The reaction mixture wasstirred for 4 h at 110° C. under N₂. The mixture was filtered and thefiltrate was concentrated. The crude product was purified by prep-TLC(Petroleum ether/EtOAc=3/1) to give the desired product Example 171h(40.0 mg, 32.4% yield) as a light yellow solid. LCMS [M+1]⁺=256.3.

Step 6: Example 171

To a solution of Example 171h (40 mg, 0.16 mmol, 1.0 eq) in dioxane (3mL) were added Example 171i (29 mg, 0.14 mol, 0.9 eq), Cs₂CO₃ (102 mg,0.31 mmol, 2.0 eq), BINAP (10 mg, 0.016 mmol, 0.1 eq) andPd₂(dba)₃.CHCl₃ (16 mg, 0.016 mmol, 0.1 eq). The reaction solution wasstirred for 6 h at. 110° C. under N₂. The reaction mixture was filteredand the filtrate was concentrated. The crude product was purified byprep-TLC (DCM/MeOH=20/1) to give the desired product Example 171 (8.2mg, 12.3% yield) as an off-white solid. LCMS [M+1]⁺=424.3. ¹H NMR (300MHz, DMSO-d₆) δ 11.05 (s, 1H), 10.90 (s, 1H), 8.89 (s, 1H), 8.57 (s,1H), 8.03 (s, 1H), 7.65 (dd, J=7.8, 1.8 Hz, 1H), 7.53 (dd, J=7.8, 1.8Hz, 1H), 7.26 (d, J=7.8 Hz, 1H), 3.96 (s, 3H), 3.72 (s, 3H), 3.11 (s,2H), 2.07-1.96 (m, 1H), 0.79 (d, J=6.0 Hz, 4H).

Example 172

Step 1: Example 172c

To a solution of Example 172a (150 mg, 0.72 mmol, 1.0 eq) in dioxane (5mL) were added Example 172b (88 mg, 0.58 mmol, 0.8 eq), Cs₂CO₃ (472 mg,1.45 mmol, 2.0 eq), BINAP (45 mg, 0.072 mmol, 0.1 eq) and Pd₂(dba)₃CHCl₃(75 mg, 0.072 mmol, 0.1 eq). The reaction mixture was stirred for 4 h at110° C. under N₂. The mixture was filtered and the filtrate wasconcentrated. The crude product was purified by prep-TLC (PetroleumEther/EtOAc=1/1) to give the desired product Example 172c (62 mg, 26.5%yield) as a yellow solid. LCMS [M+1]⁺=323.3.

Step 2: Example 172

To a solution of Example 172c (62 mg, 0.19 mmol, 1.0 eq) in dioxane (5mL) were added Example 172d (33 mg, 0.19 mol, 1.0 eq), Cs₂CO₃ (126 mg,0.39 mmol, 2.0 eq), BINAP (24 mg, 0.039 mmol, 0.2 eq) and Pd₂(dba)₃CHCl₃(20 mg, 0.019 mmol, 0.1 eq). The reaction mixture was stirred for 6 h at110° C. under N₂. The mixture was filtered and the filtrate wasconcentrated. The crude product was purified by prep-TLC (DCM/MeOH=20/1)to give the desired product Example 172 (16.1 mg, 18.3% yield) as awhite solid. LCMS [M+1]⁺=459.3. ¹H NMR (300 MHz, DMSO-d₆) δ 11.96 (s,1H), 10.02 (s, 1H), 8.95 (s, 1H), 8.92 (s, 1H), 8.67 (dd, J=4.8, 2.1 Hz,1H), 8.34 (d, J=2.4 Hz, 1H), 8.28 (dd, J=7.8, 2.1 Hz, 1H), 7.78 (dd,J=8.7, 2.4 Hz, 1H), 7.68 (d, J=8.7 Hz, 1H), 7.33 (dd, J=7.8, 4.8 Hz,1H), 5.07 (s, 1H), 3.34 (s, 3H), 3.08 (s, 2H), 1.45 (s, 6H).

Example 173

Step 1: Example 173b

To a solution of Example 173a (1.0 g, 3.7 mmol, 1.0 eq) in NaOH aqueoussolution (11.1 mL, 1M, 11.1 mmol, 3.0 eq) was added (Boc)₂O (1.29 g,5.92 mmol, 1.6 eq) in DCM (11.1 mL). The reaction mixture was stirredfor 16 h at r.t. Upon completion of the reaction, two phases wereseparated. The organic layer was washed with water (10 mL), dried overNa₂SO₄ and concentrated. The residue was purified by silica gel flashcolumn chromatography, eluted with Petroleum Ether/EtOAc (1/1) to affordthe product Example 173b (505 mg, 74% yield) as a yellow solid. LCMS[M+1]⁺=184.2.

Step 2: Example 173

To a solution of Example 173c (150 mg, 0.39 mmol, 1.0 eq,) in dioxane (5mL) were added Cs₂CO₃ (254.3 mg, 0.78 mmol, 2.0 eq), Example 173b (143.5mg, 0.78 mmol, 2.0 eq), BINAP (48.6 mg, 0.078 mmol, 0.2 eq) andPd₂(dba)₃.CHCl₃ (40.4 mg, 0.039 mmol, 0.1 eq). The reaction mixture wasstirred for 3 h at 110° C. under N₂ protection. After cooled to roomtemperature, the solvent was removed. The crude product was purified byPrep-TLC (DCM/MeOH=10/1) to afford the crude product 42 mg (90% purity),which was purified by Prep-HPLC (Prep-C18, 5 μM XBridge column, 19×150mm, Waters; gradient elution of 35% MeCN in water to 55% MeCN in waterover a 7 min period, where the aqueous phase contains 10 mM NH₄HCO₃+0.5%ammonia) to afford the product to afford the product Example 173 (14.2mg, 8% yield) as a white solid. LCMS [M+1]⁺=431.3. ¹H NMR (300 MHz,DMSO-d₆) δ 11.48 (br, 1H), 10.97 (s, 1H), 10.22 (br, 1H), 9.04 (s, 1H),8.56 (s, 1H), 7.66-7.52 (m, 2H), 7.26 (t, J=7.8 Hz, 1H), 7.01 (br, 1H),6.74 (br, 2H), 3.95 (s, 3H), 3.72 (s, 3H), 2.97-2.81 (m, 1H), 1.18-0.93(m, 4H).

Example 174

Step 1: Example 174c

To a solution of Example 174a (500 mg, 2.45 mmol) in dioxane (20 mL)were added Example 174b (417 mg, 2.45 mmol), K₂CO₃ (676 mg, 4.9 mmol),BINAP (304 mg, 0.49 mmol) and Pd₂(dba)₃CHCl₃ (252 mg, 0.25 mmol). Thereaction mixture was stirred at 90° C. for 16 h under N₂. The reactionmixture was concentrated and the crude was purified by silica gel flashcolumn chromatography (Petroleum Ether/EtOAc=2/1) to afford the productExample 174c (170 mg, 20.5% yield) as a yellow solid. LCMS [M+1]⁺=338.2.

Step 2: Example 174

To a mixture of Example 174c (170 mg, 0.5 mmol) in dioxane (5 mL) wereadded Example 174d (86 mg, 0.5 mmol), Cs₂CO₃ (326 mg, 1.0 mmol), BINAP(125 mg, 0.1 mmol) and Pd₂(dba)₃CHCl₃ (51 mg, 0.05 mmol). The reactionmixture was stirred at 110° C. for 4 h under N₂. The reaction mixturewas concentrated and the residue was purified by Prep-TLC(DCM/EtOAc=1/2) to afford the product Example 174 (66.6 mg, 28.0% yield)as a white solid. LCMS [M+1]⁺=474.3. ¹H NMR (300 MHz, DMSO-d₆) δ 12.00(s, 1H), 10.25 (s, 1H), 9.02 (s, 1H), 8.95 (s, 1H), 8.66 (dd, J=4.8, 2.1Hz, 1H), 8.29 (dd, J=7.8, 2.1 Hz, 1H), 7.99 (dd, J=10.8, 8.1 Hz, 1H),7.60 (dd, J=8.4, 1.8 Hz, 1H), 7.35 (dd, J=7.8, 1.5 Hz, 1H), 5.29 (s,1H), 3.34 (s, 3H), 3.11 (q, J=7.2 Hz, 2H), 1.48 (s, 6H), 1.13 (t, J=7.2Hz, 3H).

Example 175

Step 1: Example 175c

To a solution of Example 175a (500 mg, 2.46 mmol, 1.0 eq) in dioxane (10mL) were added K₂CO₃ (680 mg, 4.93 mmol, 2.0 eq), Example 175b (293 mg,2.46 mmol, 1.0 eq), Xantphos (285 mg, 0.493 mmol, 0.2 eq) andPd₂(dba)₃.CHCl₃ (255 mg, 0.246 mmol, 0.1 eq). The reaction mixture wasstirred for 16 h at 110° C. under N₂ protection. After the reaction wascompleted, the solvent was concentrated, and the crude product waspurified by silica gel flash column chromatography, eluted with(DCM/MeOH=30/1) to afford the product Example 175c (380 mg, 53.8% yield)as a yellow solid. LCMS [M+1]⁺=287.1.

Step 2: Example 175

To a solution of Example 175c (300 mg, 1.05 mmol, 1.0 eq) in dioxane (6mL) were added Cs₂CO₃ (683.9 mg, 2.10 mmol, 2.0 eq), Example 175d (193.5mg, 0.94 mmol, 0.9 eq), BINAP (130.7 mg, 0.21 mmol, 0.2 eq) andPd₂(dba)₃.CHCl₃ (108.5 mg, 0.105 mmol, 0.1 eq). The reaction mixture wasstirred for 4 h at 110° C. under N₂ protection. After cooled to roomtemperature, the solvent was removed. The crude product was purified bysilica gel flash column chromatography, eluted with (DCM/MeOH=20/1) toafford the product 160 mg (crude, 80% purity), which was furtherpurified by Prep-HPLC (Prep-C18, 5 μM XBridge column, 19×150 mm, Waters;gradient elution of 35% MeCN in water to 55% MeCN in water over a 7 minperiod, where the aqueous phase contains 10 mM NH₄HCO₃+0.5% ammonia) toafford the product Example 175 (58.3 mg, 12.2% yield) as a yellow solid.LCMS [M+1]⁺456.3. ¹H NMR (300 MHz, DMSO-d₆) δ 12.49 (s, 1H), 10.53 (s,1H), 9.78 (s, 1H), 8.96 (s, 1H), 8.68 (s, 1H), 8.36 (d, J=5.4 Hz, 1H),7.92 (t, J=8.1 Hz, 1H), 7.82 (d, J=8.4 Hz, 1H), 7.59 (d, J=7.2 Hz, 1H),7.50 (d, J=5.1 Hz, 1H), 4.01 (s, 3H), 3.94 (s, 3H), 3.17 (q, J=7.2 Hz,2H), 1.17 (t, J=7.2 Hz, 3H).

Example 176

Step 1: Example 176c

To a solution of Example 176a (500 mg, 2.46 mmol, 1.0 eq) dioxane (10mL) were added K₂CO₃ (680 mg, 4.93 mmol, 2.0 eq), Example 176b (293 mg,2.46 mmol, 1.0 eq), Xantphos (285 mg, 0.493 mmol, 0.2 eq) andPd₂(dba)₃.CHCl₃ (255 mg, 0.246 mmol, 0.1 eq). The reaction mixture wasstirred for 16 h at 110° C. under N₂ protection. The solvent wasconcentrated. The crude product was purified by silica gel flash columnchromatography, eluted with (DCM/MeOH=30/1) to afford the productExample 176c (310 mg, 44% yield) as a yellow solid. LCMS [M+1]⁺=287.1.

Step 2: Example 176

To a solution of Example 176c (310 mg, 1.084 mmol, 1.0 eq) in dioxane (6mL) were added Cs₂CO₃ (683.9 mg, 2.168 mmol, 2.0 eq), Example 176d(167.8 mg, 0.975 mmol, 0.9 eq), BINAP (130.7 mg, 0.217 mmol, 0.2 eq) andPd₂(dba)₃.CHCl₃ (112.2 mg, 0.108 mmol, 0.1 eq). The reaction mixture wasstirred for 4 h at 110° C. under N₂ protection. After cooled to roomtemperature, the solvent was removed. The crude product was purified bysilica gel flash column chromatography, eluted with (DCM/MeOH=15/1) toafford the crude product 120 mg (80% purity) and further purified byPrep-HPLC to afford the product Example 176 (61.1 mg, 13% yield) as anoff-white solid. LCMS [M+1]⁺=423.2. ¹H NMR (300 MHz, DMSO-d₆) δ 12.06(s, 1H), 10.54 (s, 1H), 9.19 (s, 1H), 8.97 (s, 1H), 8.77 (dd, J=4.8, 2.1Hz, 1H), 8.30 (dd, J=7.8, 1.8 Hz, 1H), 7.97-7.84 (m, 2H), 7.57 (dd,J=6.6, 1.5 Hz, 1H), 7.34 (dd, J=7.8, 4.8 Hz, 1H), 3.36 (s, 3H), 3.14 (q,J=7.2 Hz, 2H), 1.13 (t, J=7.2 Hz, 3H).

Example 177

To a solution of Example 177a (371 mg, 1.0 mmol) and Example 177b (119mg, 1.0 mmol) in dioxane (10 mL) were added Pd₂(dba)₃ (91.5 mg, 0.1mmol), Xantphos (59.5 mg, 0.1 mmol) and Cs₂CO₃ (489 mg, 1.5 mmol). Themixture was degassed by nitrogen for 3 times and stirred at 100° C. for3 h. When completed, the reaction was cooled to r.t., diluted with MeOH(5 mL) and filtered. The filtrate was purified directly by Prep-HPLC togive the desired product Example 177 (154.2 mg, 33.9% yield) as a paleyellow solid. LCMS [M+1]⁺=455.2. ¹H NMR (400 MHz, DMSO-d₆) δ 11.27 (s,1H), 10.37 (s, 1H), 8.85 (s, 1H), 8.54 (s, 1H), 7.96 (s, 1H), 7.84 (t,J=7.8 Hz, 1H), 7.74 (dd, J=17.3, 8.3 Hz, 2H), 7.58 (d, J=7.7 Hz, 1H),7.50 (d, J=7.2 Hz, 1H), 7.34 (d, J=8.6 Hz, 1H), 3.93 (s, 3H), 3.73 (s,3H), 3.09 (t, J=7.0 Hz, 2H), 1.11 (t, J=6.9 Hz, 3H).

Example 178

To a solution of Example 178a (371 mg, 1.0 mmol) and Example 178b (111mg, 1.0 mmol) in dioxane (10 mL) were added Pd₂(dba)₃ (91.5 mg, 0.1mmol), Xantphos (59.5 mg, 0.1 mmol) and Cs₂CO₃ (489 mg, 1.5 mmol). Themixture was degassed by nitrogen for 3 times and stirred at 110° C. for3 h. When completed, the reaction was cooled to r.t. diluted with MeOH(5 mL) and filtered. The filtrate was purified directly by Prep-HPLC togive the desired product Example 178 (8.4 mg, 1.9% yield) as a paleyellow solid. LCMS [M+1]⁺=447.2. ¹H NMR (400 MHz, DMSO-d₆) δ 11.09 (s,1H), 9.45 (s, 1H), 8.73 (s, 1H), 8.54 (s, 1H), 7.66 (d, J=7.4 Hz, 1H),7.57 (d, J=7.8 Hz, 2H), 7.27 (t, J=7.9 Hz, 1H), 5.90 (s, 1H), 3.93 (s,3H), 3.72 (s, 3H), 3.57 (s, 3H), 3.04-2.97 (m, 2H), 2.17 (s, 3H),1.12-1.08 (m, 3H).

Example 179

Step 1: Example 179c

To a solution of Example 179a (650 mg, 3.19 mmol, 1.0 eq) in dioxane (10mL) were added NaHCO₃ (548.7 mg, 6.38 mmol, 2.0 eq), Example 179b (354.1mg, 0.319 mmol, 1.0 eq), BINAP (398.7 mg, 0.638 mmol, 0.2 eq) andPd₂(dba)₃.CHCl₃ (331.2 mg, 0.319 mmol, 0.1 eq). The reaction mixture wasstirred for 2 h at 100 ° C. under N₂ protection. After cooled to roomtemperature, the solvent was removed, and the crude product was purifiedby silica gel flash column chromatography (Petroleum Ether/EtOAc=2/1) toafford the product Example 179c (250 mg, 28% yield) as a yellow solid.LCMS [M+1]⁺=279.2.

Step 2: Example 179

To a solution of Example 179c (250 mg, 0.899 mmol, 1.0 eq) in dioxane (5mL) were added Cs₂CO₃ (586 mg, 1.80 mmol, 2.0 eq), Example 179d (139 mg,0.809 mmol, 0.9 eq), BINAP (112 mg, 0.180 mmol, 0.2 eq) andPd₂(dba)₃.CHCl₃ (90 mg, 0.087 mmol, 0.1 eq). The reaction mixture wasstirred for 4 h at 110° C. under N₂ protection. After cooled to roomtemperature, the solvent was removed. The crude product was purified bysilica gel flash column chromatography, eluted with DCM/MeOH (20/1) toafford the crude product 140 mg (90% purity) and further purified byPrep-HPLC to afford the product Example 179 (84.6 mg, 23% yield) as anoff-white solid. LCMS [M+1]⁺=415.3. H NMR (300 MHz, DMSO-d₆) δ 11.98 (s,1H), 9.64 (s, 1H), 8.83 (s, 1H), 8.65 (dd, J=4.8, 1.8 Hz, 1H), 8.53(brs, 1H), 8.27 (dd, J=7.8, 2.1 Hz, 1H), 7.31 (dd, J=7.8, 4.8 Hz, 1H),6.11 (s, 1H), 3.64 (s, 3H), 3.33 (s, 3H), 3.06 (q, J=7.2 Hz, 2H), 2.24(s, 3H), 1.11 (t, J=7.2 Hz, 3H).

Example 180

Step 1: Example 180c

To a solution of Example 180a (1.0 g, 4.9 mmol, 1.0 eq) in dioxane (20mL) were added NaHCO₃ (842.8 mg, 9.8 mmol, 2.0 eq), Example 180b (543.9mg, 4.9 mmol, 1.0 eq), BINAP (610.5 mg, 0.98 mmol, 0.2 eq) andPd₂(dba)₃.CHCl₃ (507.2 mg, 0.49 mmol, 0.1 eq). The reaction mixture wasstirred for 2 h at 100° C. under N₂ protection. After cooled to roomtemperature, the solvent was removed, and the crude product was purifiedby silica gel flash column chromatography (Petroleum Ether/EtOAc=2/1) toafford the product Example 180c (380 mg, 28% yield) as a yellow solid.LCMS [M+1]⁺=279.2.

Step 2: Example 180

To a solution of Example 180c (340 mg, 1.22 mmol, 1.0 eq) in dioxane (5mL) were added Cs₂CO₃ (795.4 mg, 2.44 mmol, 2.0 eq), Example 180d (226.6mg, 0.32 mmol, 1.1 eq), BINAP (152.0 mg, 0.24 mmol, 0.2 eq) andPd₂(dba)₃.CHCl₃ (126.3 mg, 0.12 mmol, 0.1 eq). The reaction mixture wasstirred for 4 h at 110° C. under N₂ protection. After cooled to roomtemperature, the solvent was removed. The crude product was purified bysilica gel flash column chromatography (DCM/MeOH=20/1) to afford thecrude product (220 mg) and further purified by Prep-HPLC (Prep-C18, 5 μMXBridge column, 19×150 mm, Waters; gradient elution of 35% MeCN in waterto 55% MeCN in water over a 7 min period, where the aqueous phasecontains 10 mM NH₄HCO₃+0.5% ammonia) to afford the product Example 180(61.9 mg, 11% yield) as a white solid. LCMS [M+1]⁺=448.3. ¹H NMR (300MHz, DMSO-d₆) δ 12.38 (s, 1H), 9.61 (s, 1H), 9.00 (s, 1H), 8.83 (s, 1H),8.67 (s, 1H), 8.16 (d, J=5.4 Hz, 1H), 7.47 (d, J=5.1 Hz, 1H), 6.13 (s,1H), 4.01 (s, 3H), 3.92 (s, 3H), 3.68 (s, 3H), 3.08 (q, J=7.2 Hz, 2H),2.26 (s, 3H), 1.15 (t, J =7.2 Hz, 3H).

Example 181

Step 1: Example 181c

To a solution of Example 181a (1 g, 10.0 mmol) in dioxane (15 mL) wereadded Example 181b (2 g, 14.6 mmol), and TEA (2 g, 19.8 mmol). Thereaction mixture was stirred at room temperature for 16 h. Then themixture was diluted with EtOAc, washed by water, brine, and dried overanhydrous Na₂SO₄. The solution was concentrated to afford crude residue,which was purified by silica gel flash column chromatography (PetroleumEther/EtOAc=1/1) to afford the product Example 181c (1 g, 69.8% yield)as a white solid.

Step 2: Example 181

To a solution of Example 181d (100 mg, 0.26 mmol) and Example 181c (38.3mg, 0.26 mmol) in DMA (2.5 mL) were added Pd₂(dba)₃ (24 mg, 0.0126mmol), Xantphos (15.6 mg, 0.026 mmol) and Cs₂CO₃ (172 mg, 0.53 mmol).The mixture was degassed by nitrogen for 3 times and stirred at 130° C.for 2 h. When completed, the reaction was cooled to r.t., diluted withMeOH (5 mL) and filtered. The filtrate was purified directly byPrep-HPLC to give the desired product Example 181 (24.3 mg, 18.9% yield)as a off white solid. LCMS [M+1]⁺=484.3. ¹H NMR (400 MHz, Chloroform-d)δ 11.33 (s, 1H), 10.08 (s, 1H), 9.43 (s, 1H), 8.96 (s, 1H), 8.41 (s,1H), 8.04 (d, J=7.8 Hz, 1H), 7.91 (d, J=7.8 Hz, 1H), 7.66 (t, J=7.9 Hz,1H), 4.41 (s, 2H), 4.35 (s, 3H), 4.18 (s, 2H), 4.13 (s, 3H), 3.40 (d,J=9.1 Hz, 1H), 2.91 (s, 6H).

Example 182

Step 1: Example 182c

To a solution of Example 182a (400 mg, 2.65 mmol) in dioxane (5 mL) wereadded Example 182b (365 mg, 2.56 mmol), and TEA (795 mg, 7.87 mmol). Thereaction mixture was stirred at room temperature overnight. Then themixture was used directly in the next step.

Step 2: Example 182d

To a solution of Example 182c in dioxane was added Boc₂O (687 mg, 3.18mmol), followed by addition of Na₂CO₃ (687 mg in 5 mL of H₂O). Themixture was stirred at room temperature overnight. Then the mixture wasextracted by EtOAc, dried over anhydrous Na₂SO₄, concentrated, andpurified by silica gel flash column chromatography, eluted with DCM/MeOH(10/1) to afford the product Example 182d (170 mg, 27.8% yield) as awhite solid.

Step 3: Example 182f

To a solution of Example 182e (75 mg, 0.2 mmol,) in dioxane (5 mL) wereadded Example 182d (46 mg, 0.2 mmol), Pd₂(dba)₃ (18 mg, 0.02 mmol),Xantphos (13 mg, 0.02 mmol) and Cs₂CO₃ (130 mg, 0.4 mmol). The mixturewas sealed and heated to 110° C. for 3 h. The mixture was filtrated andconcentrated under reduced pressure to give crude Example 182f (200 mg,quant.) which was used for the next step directly without purification.

Step 4: Example 182

To a solution of Example 182f (200 mg, crude 0.2 mmol) in DCM (5 mL) wasadded TFA (2 mL). The mixture was stirred at room temperature for 2 h,then the mixture was concentrated, and purified by Prep-HPLC to giveExample 182 (15.7 mg, 9.5% yield) as a white solid. LCMS [M+1]⁺=477.2.¹H NMR (400 MHz, DMSO-d₆) δ 10.99 (s, 1H), 9.73 (s, 1H), 9.05 (s, 1H),8.54 (s, 1H), 8.33 (s, 2H), 7.74-7.62 (m, 2H), 7.48 (d, J=7.8 Hz, 1H),7.25 (t, J=7.8 Hz, 1H), 4.04 (d, J=9.3 Hz, 2H), 3.92 (s, 4H), 3.67 (s,3H), 3.53 (d, J=7.6 Hz, 2H), 2.93 (s, 1H), 1.48 (s, 3H), 1.15-0.99 (m,4H).

Example 183

Step 1: Example 183c

To a solution of Example 183a (61 mg, 0.27 mmol) in dioxane (5 mL) wereadded Example 183b (100 mg, 0.27 mmol), Pd₂(dba)₃ (24 mg, 0.027 mmol),Xantphos (16 mg, 0.027 mmol) and Cs₂CO₃ (173 mg, 0.53 mmol). The mixturewas sealed and heated to 110° C. for overnight. The mixture wasfiltrated and concentrated under reduced pressure to give crude Example183c (170 mg), which was used for the next step directly withoutpurification.

Step 2: Example 183

To a solution of Example 183c (170 mg, crude 0.27 mmol) in DCM (5 mL)was added TFA (2 mL). The mixture was stirred at room temperature for 2h. Then the mixture was concentrated, and purified by Prep-HPLC to giveExample 183 (14.6 mg, 10.4% yield) as a yellow solid. LCMS [M+1]⁺=470.2.¹H NMR (400 MHz, Methanol-d₆) δ 8.48 (s, 1H), 7.86 (s, 1H), 7.69 (d,J=7.9 Hz, 1H), 7.58 (d, J=8.0 Hz, 1H), 7.29 (t, J=8.2 Hz, 1H), 4.19-4.11(m, 4H), 4.02 (s, 3H), 3.73 (s, 3H), 1.64 (s, 3H).

Example 184

To a solution of Example 184a (50 mg, 0.15 mmol, 1.0 eq) in dioxane (2mL) were added Example 184b (25 mg, 0.15 mmol, 1.0 eq), Cs₂CO₃ (96 mg,0.29 mmol, 2.0 eq), BINAP (18 mg, 0.029 mmol, 0.2 eq) and Pd₂(dba)₃CHCl₃(15 mg, 0.015 mmol, 0.1 eq). The reaction mixture was stirred for 4 h at110° C. under N₂. The solid was filtered out and the filtrate wasconcentrated. The crude product was purified by Prep-TLC (DCM/MeOH=20/1)to give the desired product Example 184 (23.5 mg, 33.6% yield) as alight yellow solid. LCMS [M+1]⁺=477.3. ¹H NMR (300 MHz, DMSO-d₆) δ 12.00(s, 1H), 10.25 (s, 1H), 9.02 (s, 1H), 8.95 (s, 1H), 8.66 (dd, J=4.8, 2.1Hz, 1H), 8.29 (dd, J=7.8, 1.8 Hz, 1H), 7.99 (dd, J=10.8, 8.4 Hz, 1H),7.62 (d, J=7.8 Hz, 1H), 7.35 (dd, J=7.8, 4.5 Hz, 1H), 5.29 (s, 1H), 3.34(s, 3H), 3.09 (s, 2H), 1.48 (s, 6H).

Example 185

To a solution of Example 185a (50 mg, 0.15 mmol, 1.0 eq) in dioxane (2mL) were added Example 185b (30 mg, 0.15 mmol, 1.0 eq), Cs₂CO₃ (96 mg,0.29 mmol, 2.0 eq), BINAP (18 mg, 0.029 mmol, 0.2 eq) and Pd₂(dba)₃CHCl₃(15 mg, 0.015 mmol, 0.1 eq). The reaction solution was stirred for 4 hat 110° C. under N₂. The mixture was filtered and the filtrate wasconcentrated. The crude product was purified by prep-TLC (DCM/MeOH=20/1)to give the desired product Example 185 (35.0 mg, 46.8% yield) as alight yellow solid. LCMS [M+1]⁺=510.4. ¹H NMR (300 MHz, DMSO-d₆) δ 12.38(s, 1H), 10.25 (s, 1H), 9.53 (s, 1H), 8.94 (s, 1H), 8.68 (s, 1H), 8.18(d, J=5.1 Hz, 1H), 8.00 (dd, J=10.8, 8.4 Hz, 1H), 7.59 (d, J=8.1 Hz,1H), 7.52 (d, J=5.1 Hz, 1H), 5.29 (s, 1H), 4.01 (s, 3H), 3.93 (s, 3H),3.11 (s, 2H), 1.50 (s, 6H).

Example 188

To a solution of Example 188a (100 mg, 0.27 mmol) and Example 188b (30mg, 0.27 mmol) in dioxane (10 mL) were added Pd₂(dba)₃ (24.6 mg, 0.027mmol), Xantphos (16 mg, 0.027 mmol) and Cs₂CO₃ (131 mg, 0.40 mmol). Themixture was degassed by nitrogen for 3 times and stirred at 110° C. for4 h. When completed, the reaction was cooled to r.t, diluted with EtOAc(5 mL) and filtered. The filtrate was purified directly by Prep-HPLC togive the desired product Example 188 (27.5 mg, 22.4% yield) as a paleyellow solid. LCMS [M+1]⁺=445.2. ¹H NMR (400 MHz, DMSO-d₆) δ 11.07 (s,1H), 10.19 (s, 1H), 8.85 (s, 1H), 8.55 (s, 1H), 7.97 (d, J=9.2 Hz, 1H),7.67-7.61 (m, 3H), 7.43 (d, J=9.2 Hz, 1H), 7.25 (t, J=8.0 Hz, 1H), 3.94(s, 3H), 3.73 (s, 3H), 3.08 (q, J=7.6 Hz, 2H), 1.11 (t, J=7.1 Hz, 3H).

Example 189

To a solution of Example 189b (869 mg, 3.45 mmol, 1.1 eq) in dioxane(100 mL) were added Example 189a (650 mg, 3.14 mmol, 1.0 eq), Cs₂CO₃(2.04 g, 6.27 mmol, 2.0 eq), BINAP (391 mg, 0.63 mmol, 0.2 eq) andPd₂(dba)₃CHCl₃ (325 mg, 0.31 mmol, 0.1 eq). The reaction solution wasstirred for 4 h at 110° C. under N₂. The solvent was concentrated, andthe residue was purified by silica gel flash column chromatography,eluted with DCM/MeOH (v/v=25/1) to give the desired product Example 189(1.1 g, crude, 85% purity) as a yellow solid and further purified byreverse phase preparative HPLC to give the desired product Example 189(512.6 mg, 38.6% yield) as a white solid. LCMS [M+1]⁺=424.4. ¹H NMR (300MHz, DMSO-d₆) δ 11.05 (s, 1H), 10.90 (s, 1H), 8.89 (s, 1H), 8.56 (s,1H), 8.04 (s, 1H), 7.65 (dd, J=7.8, 1.8 Hz, 1H), 7.53 (dd, J=8.1, 1.5Hz, 1H), 7.26 (t, J=7.8 Hz, 1H), 3.72 (s, 3H), 3.13 (q, J=7.2 Hz, 2H),2.10-1.94 (m, 1H), 1.13 (t, J=7.2 Hz, 3H), 0.79 (d, J=6.0 Hz, 4H).

Example 190

Step 1: Example 190c

To a solution of Example 190a (150 mg, 0.73 mmol, 1.0 eq) and Example190b (79 mg, 0.73 mmol, 1.0 eq) in dioxane (3 mL) were added K₂CO₃ (201mg, 1.46 mmol, 2.0 eq), Pd₂(dba)₃.CHCl₃ (75 mg, 0.073 mmol, 0.1 eq) andBINAP (15.0 mg, 0.15 mmol, 0.2 eq). The reaction mixture was stirred for16 h at 80° C. under N₂ protection. The reaction solution was filteredand the filtrate was concentrated in vacuum. The crude product waspurified by silica gel flash column chromatography (PetroleumEther/EtOAc=1/1) to afford the desired product Example 190c (65 mg,32.0% yield) as a yellow solid. LCMS [M+1]⁺=280.2.

Step 2: Example 190

To a solution of Example 190c (60 mg, 0.22 mmol, 1.0 eq) in dioxane (3mL) and Example 190d (37 mg, 0.22 mmol, 1.0 eq) were added Cs₂CO₃ (139.7mg, 0.44 mmol, 2.0 eq), Pd₂(dba)₃.CHCl₃ (22.2 mg, 0.022 mmol, 0.1 eq)and BINAP (25 mg, 0.044 mmol, 0.2 eq). The reaction mixture was stirredfor 4 h at 110° C. under N₂ protection. The mixture was filtered and thefiltrate was concentrated in vacuum. The crude product was purified byprep-TLC (DCM/MeOH=30/1) to afford the desired product Example 190 (9.2mg, 10.3% yield) as a light yellow solid. LCMS [M+1]⁺=416.3. ¹H NMR (300MHz, DMSO-d₆) δ 11.94 (s, 1H), 10.41 (s, 1H), 8.94 (s, 1H), 8.73 (s,1H), 8.67-8.59 (m, 1H), 8.29 (d, J=8.1 Hz, 1H), 8.09 (d, J=9.0 Hz, 1H),7.49 (d, J=9.0 Hz, 1H), 7.34 (dd, J=7.8, 4.8 Hz, 1H), 3.35 (s, 3H), 3.09(s, 2H), 2.54 (s, 3H).

Example 191

Step 1: Example 191c

To a solution of Example 191a (150 mg, 0.73 mmol, 1.0 eq) and Example191b (89.5 mg, 0.73 mmol, 1.0 eq) in dioxane (10 mL) were added K₂CO₃(201 mg, 1.46 mmol, 2.0 eq), Pd₂(dba)₃.CHCl₃ (75.3 mg, 0.073 mmol, 0.1eq) and BINAP (90.6 mg, 0.15 mmol, 0.2 eq). The reaction mixture wasstirred for 16 h at 80° C. under N₂ protection. The mixture was filteredand the filtrate was concentrated in vacuum. The crude product waspurified by silica gel flash column chromatography (DCM/MeOH=40/1) toafford the desired product Example 191c (60 mg, 28.4% yield) as a yellowsolid. LCMS [M+1]⁺=294.2.

Step 2: Example 191

To a solution of Example 191c (60 mg, 0.22 mmol, 1.0 eq) and Example191d (35 mg, 0.22 mmol, 1.0 eq) in dioxane (3 mL) were added Cs₂CO₃ (132mg, 0.44 mmol, 20 eq), Pd₂(dba)₃.CHCl₃ (21 mg, 0.022 mmol, 0.1 eq) andBINAP (25.4 mg, 0.044 mmol, 0.2 eq). The reaction mixture was stirredfor 4 h at 110° C. under N₂ protection. The mixture was filtered and thefiltrate was concentrated in vacuum. The crude product was purified byprep-TLC (DCM/MeOH=30/1) to afford the desired product Example 191 (19.2mg, 22.3% yield) as a light yellow solid. LCMS [M+1]⁺=430.3. ¹H NMR (300MHz, DMSO-d₆) δ 11.97 (s, 1H), 10.35 (s, 1H), 9.07 (s, 1H), 8.98 (s,1H), 8.68 (dd, J=4.8, 1.8 Hz, 1H), 8.30 (dd, J=7.8, 1.8 Hz, 1H),7.43-7.30 (m, 2H), 3.35 (s, 3H), 3.11 (s, 2H), 2.44 (s, 3H), 2.33 (s,3H).

Example 193

To a solution of Example 193a (750 mg, 2.93 mmol, 1.0 eq) in dioxane (25mL) were added Example 193b (900 mg, 4.39 mmol, 1.5 eq), Cs₂CO₃ (1.91 g,5.86 mmol, 2.0 eq), BINAP (365 mg, 0.59 mmol, 0.2 eq) and Pd₂(dba)₃CHCl₃(303 mg, 0.29 mmol, 0.1 eq). The reaction solution was stirred for 6 hat 110° C. under N₂. The reaction solution was concentrated and theresidue was purified by silica gel flash column chromatography, elutedwith DCM/MeOH (v/v=20/1) to give the desired product Example 193 (411.8mg, 33.1% yield) as a light yellow solid. LCMS [M+1]⁺=425.3. ¹H NMR (300MHz, DMSO-d₆) δ 12.36 (s, 1H), 10.91 (s, 1H), 9.71 (s, 1H), 8.96 (s,1H), 8.67 (s, 1H), 8.14 (d, J=5.1 Hz, 1H), 7.50 (d, J=5.1 Hz, 1H), 4.00(s, 3H), 3.92 (s, 3H), 3.14 (s, 2H), 2.13-2.01 (m, 1H), 0.91-0.79 (m,4H).

Example 195

To a solution of Example 195b (700 mg, 2.73 mmol, 1.0 eq) dioxane (20mL) were added Cs₂CO₃ (1.8 g, 5.46 mmol, 2.0 eq), Example 195a (847.6mg, 4.09 mmol, 1.5 eq), BINAP (340.2 mg, 0.55 mmol, 0.2 eq) andPd₂(dba)₃.CHCl₃ (279.5 mg, 0.27 mmol, 0.1 eq). The reaction mixture wasstirred for 4 h at 110° C. under N₂ protection. After cooled to roomtemperature, the solvent was removed. The crude product was purified bysilica gel flash column chromatography (DCM/MeOH=20/1) to afford thecrude product 1.2 g, which was further purified by Prep-HPLC (Prep-C18,5 μM XBridge column, 19×150 mm, Waters; gradient elution of 35% MeCN inwater to 55% MeCN in water over a 7 min period, where the aqueous phasecontains 10 mM NH₄HCO₃+0.5% ammonia) to afford the product Example 195(401.9 mg, 35% yield) as an off-white solid. LCMS [M+1]⁺=427.3. ¹H NMR(300 MHz, DMSO-d₆) δ 11.05 (s, 1H), 10.89 (s, 1H), 8.89 (s, 1H), 8.56(s, 1H), 8.03 (s, 1H), 7.65 (dd, J=7.8, 1.5 Hz, 1H), 7.53 (dd, J=7.8.1.5 Hz, 1H), 7.26 (t, J=7.8 Hz, 1H), 3.72 (s, 3H), 3.11 (s, 2H),2.08-1.95 (m, 1H), 0.79 (d, J =6.3 Hz, 4H).

Example 196

Step 1: Example 196b

To a solution of Example 196a (100 mg, 0.75 mmol, 1.0 eq) in 1M NaOHaqueous solution (2.25 mL, 2.25 mmol, 3.0 eq) was added a solution of(Boc)₂O (261.6 mg, 1.2 mmol, 1.6 eq) in DCM (5 mL). The reaction mixturewas stirred for 16 h at r.t. Upon completion of the reaction, two phaseswere separated. The organic layer was washed with water (5 mL), driedover Na₂SO₄ and concentrated. The crude product was purified by Prep-TLC(DCM/MeOH=20/1) to afford the product Example 196b (78 mg, 53% yield) asyellow oil. LCMS [M+1]⁺=198.2.

Step 2: Example 196

To a solution of Example 196c (50 mg, 0.13 mmol, 1.0 eq.) in DMA (2 mL)were added Cs₂CO₃ (84.8 mg, 0.26 mmol, 2.0 eq), Example 196b (51 mg,0.26 mmol, 2.0 eq), BINAP (16.2 mg, 0.03 mmol, 0.2 eq) andPd₂(dba)₃.CHCl₃ (13.5 mg, 0.01 mmol, 0.1 eq). The reaction mixture wasstirred for 2 h at 110° C. under N₂ protection. After cooled to roomtemperature, the reaction was diluted with EtOAc (20 mL), washed withbrine, dried over Na₂SO₄ and concentrated. The crude product waspurified by Prep-TLC (DCM/MeOH=10/1) to afford the product Example 196(9.1 mg, 16% yield) as a yellow solid. LCMS [M+1]⁺=445.3. ¹H NMR (300MHz, DMSO-d₆) δ 11.10 (br, 1H), 10.98 (s, 1H), 10.03 (brs, 1H), 9.04 (s,1H), 8.56 (s, 1H), 7.61 (d, J=8.1 Hz, 2H), 7.26 (t, J=7.8 Hz, 1H), 7.08(brs, 1H), 6.45 (brs, 1H), 3.95 (s, 3H), 3.71 (s, 3H), 2.95-2.81 (m,1H), 2.09 (s, 3H), 1.12-0.96 (m, 4H).

Example 198

Step 1: Example 198

To a solution of Example 198a (200 mg, 0.97 mmol, 1.0 eq) in dioxane (5mL) were added K₂CO₃ (267.7 mg, 1.94 mmol, 2.0 eq), Example 198b (115.4mg, 0.97 mmol, 1.0 eq) and Xantphos (112.3 mg, 0.194 mmol, 0.2 eq) andPd₂(dba)₃.CHCl₃ (100.4 mg, 0.097 mmol, 0.1 eq). The reaction mixture wasstirred for 6 h at 110° C. under N₂ protection. After cooled to roomtemperature, the solvent was removed. The crude product was purified bysilica gel flash column chromatography (DCM/MeOH=20/1) to afford theproduct Example 198c (120 mg, 43% yield) as a yellow solid.

LCMS [M+1]⁺=290.2

Step 2: Example 198

To a solution of Example 198c (60 mg, 0.21 mmol, 1.0 eq) in dioxane (3mL) were added Cs₂CO₃ (136.9 mg, 0.42 mmol, 2.0 eq), Example 198d (65.2mg, 0.32 mmol, 1.5 eq), BINAP (26.2 mg, 0.042 mmol, 0.2 eq) andPd₂(dba)₃.CHCl₃ (21.7 mg, 0.021 mmol, 0.1 eq). The reaction mixture wasstirred for 4 h at 110° C. under N₂ protection. After cooled to roomtemperature, the solvent was removed. The crude product was purified byPrep-TLC (DCM/MeOH=15/1) to afford the product 60 mg crude product,which was further purified by Prep-HPLC (Prep-C18, 5 μXBridge column,19×150 mm, Waters; gradient elution of 35% MeCN in water to 55% MeCN inwater over a 7 min period, where the aqueous phase contains 10 mMNH₄HCO₃+0.5% ammonia) to afford the product Example 198 (15.4 mg, 16%yield) as an off-white solid. LCMS [M+1]⁺=461.3. ¹H NMR (300 MHz,DMSO-d₆) δ 11.29 (s, 1H), 10.40 (brs, 1H), 8.90 (s, 1H), 8.57 (s, 1H),7.99 (s, 1H), 7.92-7.86 (m, 1H), 7.85-7.71 (m, 2H), 7.62 (dd, J=8.1, 1.8Hz, 1H), 7.54 (d, J=7.2 Hz, 1H), 7.38 (t, J=7.8 Hz, 1H), 3.76 (s, 3H),3.10 (s, 2H).

Example 199

To a solution of Example 199a (60 mg, 0.204 mmol, 1.2 eq) in dioxane (3mL) were added Cs₂CO₃ (110.8 mg, 0.34 mmol, 2.0 eq), Example 199b (35mg, 0.17 mmol, 1.0 eq), BINAP (21.2 mg, 0.034 mmol, 0.2 eq) andPd₂(dba)3CHCl3 (17.6 mg, 0.017 mmol, 0.1 eq). The reaction mixture wasstirred for 4 h at 110° C. under N₂ protection. After cooled to roomtemperature, the solvent was removed. The crude product was purified byPrep-TLC (DCM/MeOH=15/1) to afford the product Example 199 (19.3 mg,2.4% yield) a yellow solid. LCMS [M+1]⁺=462.3. ¹H NMR (300 MHz, DMSO-d₆)δ 12.48 (s, 1H), 10.52 (s, 1H), 9.78 (s, 1H), 8.96 (s, 1H), 8.67 (s,1H), 8.36 (d, J=5.1 Hz, 1H), 7.92 (t, J=8.1 Hz, 1H), 7.82 (d, J=8.4 Hz,1H), 7.59 (d, J=6.9 Hz, 1H), 7.50 (d, J=5.4 Hz, 1H), 3.94 (s, 3H), 3.13(s, 2H).

Example 200

Step 1: Example 200b

To a solution of Example 200a (3.2 g, 18.93 mmol, 1.0 eq) in EtOH (20mL) and H₂O (4 mL) was added NaOH (908 mg, 22.72 mmol, 1.2 eq) at r.t.The mixture was stirred for 1 h at 50° C. After the reaction wascompleted, the solvent was removed. The crude product was purified bysilica gel flash column chromatography (Petroleum Ether/EtOAc=20/1) toafford the product Example 200b (1.2 g, 33.9% yield) as a white solid.LCMS [M+1]⁺=187.2.

Step 2: Example 200c

A solution of Example 200b (1.2 g, 6.45 mmol, 1.0 eq) in DMF-DMA (3.07g, 25.8 mmol, 4.0 eq) was stirred for 2 h at 95° C. After the reactioncompleted, it was concentrated under vacuum. The residue was dissolvedin AcOH (5 mL) and EtOH (20 mL), and N₂H₄.H₂O (3.2 g, 80% in water, 51.6mmol, 8.0 eq) was added dropwise at 0° C. The reaction mixture wasstirred for 2 h at r.t. After completion, the mixture was concentratedin vacuo. The crude product was purified by silica gel flash columnchromatography (DCM/MeOH=20/1) to afford the product Example 200c (600mg, 44.4% yield) as a white solid. LCMS [M+1]⁺=211.2.

Step 3: Example 200d

To a solution of Example 200c (600 mg, 2.86 mmol, 1.0 eq) in DMF (10 mL)were added K₂CO₃ (789 mg, 5.72 mmol, 2.0 eq) and CD₃I (621 mg, 4.29mmol, 1.5 eq) at 0° C. The reaction mixture was stirred for 4 h at r.t.The reaction was diluted with EtOAc and washed with brine. The organiclayer was dried over Na₂SO₄ and concentrated. The residue was purifiedby silica gel flash column chromatography, eluted with PetroleumEther/EtOAc (v/v 1/3) to afford the product Example 200d (550 mg, 84.8%yield) as a yellow solid. LCMS [M+1]⁺=228.2.

Step 4: Example 200f

To a solution of Example 200d (550 mg, 2.42 mmol, 1.0 eq) in dioxane (10mL) were added Cs₂CO₃ (1.57 g, 4.84 mmol, 2.0 eq), Example 200e (399 mg,2.9 mmol, 1.2 eq), BINAP (302 mg, 0.48 mmol, 0.2 eq) and Pd₂(dba)₃.CHCl₃(251 mg, 024 mmol, 0.1 eq). The reaction mixture was stirred for 3 h at110° C. under N₂ protection. After the reaction was completed, thesolvent was removed, and the residue was purified by silica gel flashcolumn chromatography (DCM/MeOH=20/1) to afford the product Example 200f(505 mg, 63.5% yield) as a yellow solid. LCMS [M+1]⁺=329.3.

Step 5: Example 200g

The solution of Example 200f (505 mg, 1.54 mmol, 1.0 eq) in TFA (20 mL)was stirred for 1 h at 70° C. After the reaction was completed, it wasconcentrated in vacuum. The residue was dissolved in MeOH (20 mL) andbasified with NaHCO₃ (910 mg, 8.58 mmol, 2.0 eq). The solid was filteredout, and the filtrate was concentrated in vacuum. The residue waspurified by silica gel flash column chromatography (DCM/MeOH=20/1) toafford the product Example 200g (180 mg, 56.3% yield) as a light graysolid. [M+1]⁺=209.4.

Step 6: Example 200

To a solution of Example 200g (40 mg, 0.19 mmol, 1.0 eq) and Example200h (59.1 mg, 0.23 mmol, 1.2 eq) in dioxane (2 mL) were added Cs₂CO₃(125 mg, 0.38 mmol, 2.0 eq), Pd₂(dba)₃.CHCl₃ (19.9 mg, 0.019 mmol, 0.1eq) and BINAP (23.9 mg, 0.038 mmol, 0.2 eq). The reaction mixture wasstirred for 3 h at 110° C. under N₂ protection. The mixture was filteredand the filtrate was concentrated in vacuum. The crude product waspurified by prep-TLC (DCM/MeOH=30/1) to afford the desired productExample 200 (19.6 mg, 23.9% yield) as a light yellow solid. LCMS[M+1]⁺=428.3. ¹H NMR (300 MHz, DMSO-d₆) δ 12.36 (s, 1H), 10.90 (s, 1H),9.71 (s, 1H), 8.96 (s, 1H), 8.67 (s, 1H), 8.14 (d, J=5.1 Hz, 1H), 7.50(d, J=5.1 Hz, 1H), 3.92 (s, 3H), 3.14 (s, 2H), 2.06-2.08 (m, 1H),0.83-0.88 (m, 4H).

Example 201

Step 1: Example 201c

To a solution of Example 201a (1.7 g, 8.21 mmol, 1.0 eq) and Example201b (1.39 g, 8.21 mmol, 1.0 eq) in dioxane (25 mL) were added NaHCO₃(1.38 g, 16.4 mmol, 2.0 eq), Pd₂(dba)₃.CHCl₃ (850 mg, 0.82 mmol, 0.1 eq)and BINAP (15.0 mg, 1.64 mmol, 0.2 eq). The reaction mixture was stirredfor 16 h at 100° C. under N₂ protection. The mixture was filtered andthe filtrate was concentrated in vacuum. The crude product was purifiedby silica gel flash column chromatography (Petroleum Ether/EtOAc=1/1) toafford the desired product Example 201c (1.01 g, 36.2% yield) as a lightbrown solid. LCMS [M+1]⁺=341.3.

Step 2: Example 201

To a solution of Example 201c (78.7 mg, 0.23 mmol, 1.2 eq) and Example201d (40 mg, 0.19 mmol, 1.0 eq) in dioxane (2 mL) were added Cs₂CO₃ (125mg, 0.38 mmol, 2.0 eq), Pd₂(dba)₃.CHCl₃ (19.9 mg, 0.019 mmol, 0.1 eq)and BINAP (23.9 mg, 0.038 mmol, 0.2 eq). The reaction mixture wasstirred for 4 h at 110° C. under N₂ protection. The mixture was filteredand the filtrate was concentrated in vacuum. The crude product waspurified by prep-TLC (DCM/MeOH=30/1) to afford the desired productExample 201 (18.9 mg, 19.3% yield) as a light yellow solid. LCMS[M+1]⁺=513.4. ¹H NMR (300 MHz, DMSO-d₆) δ 12.38 (s, 1H), 10.24 (s, 1H),9.53 (s, 1H), 8.94 (s, 1H), 8.67 (s, 1H), 8.18 (d, J=5.4 Hz, 1H), 8.00(dd, J=10.8, 8.4 Hz, 1H), 7.60 (dd, J=8.4, 1.8 Hz, 1H), 7.51 (d, J=5.1Hz, 1H), 5.29 (s, 1H), 3.93 (s, 3H), 3.11 (s, 2H), 1.50 (s, 6H).

Example 202

To a solution of Example 202b (750 mg, 2.20 mmol, 1.0 eq) dioxane (25mL) were added Example 202a (546 mg, 2.64 mmol, 1.2 eq), Cs₂CO₃ (1.43 g,4.40 mmol, 2.0 eq), BINAP (274 mg, 0.44 mmol, 0.2 eq) and Pd₂(dba)₃CHCl₃(228 mg, 0.22 mmol, 0.1 eq). The reaction mixture was stirred for 4 h at110° C. under N₂. The solvent was concentrated; the residue was purifiedby silica gel flash column chromatography, eluted with DCM/MeOH(v/v=20/1) to give the desired product Example 202 (401.3 mg, 35.67%yield) as a light yellow solid. LCMS [M+1]⁺=512.4. ¹H NMR (300 MHz,DMSO-d₆) δ 11.15 (s, 1H), 10.11 (s, 1H), 8.87 (s, 1H), 8.57 (s, 1H),7.96 (dd, J=10.8, 8.4 Hz, 1H), 7.79 (s, 1H), 7.73 (dd, J=8.4, 1.5 Hz,2H), 7.63 (dd, J=7.8, 1.8 Hz, 1H), 7.49 (dd, J=8.1, 1.81 Hz, 1H), 7.28(t, J=7.8 Hz, 1H), 5.26 (s, 1H), 3.76 (s, 3H), 3.08 (s, 2H), 1.46 (s,6H).

Example 203

Step 1: Example 203b

To a solution of Example 203a (50.0 g, 0.446 mol, 1.0 eq) in ACN (1000mL) was added NBS (87.0 g, 0.491 mol, 1.1 eq) at 0° C. under N₂protection. The reaction solution was stirred for 1 h at r.t. Thesolvent was concentrated under vacuum. The residue was purified bysilica gel flash column chromatography (Petroleum Ether/EtOAc=5/1) toafford the product Example 203b (68.1 g, 80.3% yield) as a white solid.LCMS [M+1]⁺=191.2.

Step 2: Example 203c

To a solution of Example 211b (10.0 g, 52.63 mmol, 1.0 eq) in THF (200mL) was added n-BuLi (73.68 mL, 2.5 M in hexane, 184.21 mmol, 3.5 eq)dropwise at −78° C. under N₂. The reaction was stirred for 30 min at thesame temperature; A solution of Acetone-d₆ (16.84 g, 263.16 mmol, 5.0eq) in THF (30 mL) was added dropwise at −78° C. The reaction mixturewas stirred for 30 min at r.t. and then quenched with saturated aqueousof NH₄Cl (200 mL) and extracted with EtOAc (300 mL*3). The combinedorganic layers were washed with brine (500 mL), dried over Na₂SO₄ andconcentrated. The residue was purified by silica gel flash columnchromatography eluted with Petroleum Ether/EtOAc (1/1) to give thedesired product Example 203c (5.9 g, 64.0% yield) as a yellow solid.LCMS [M+1]⁺=177.2.

Step 3: Example 203e

To a solution of Example 203d (2.0 g, 9.66 mmol, 1.0 eq) in dioxane (50mL) were added Example 203c (1.71 g, 9.66 mol, 1.0 eq), NaHCO₃ (1.62 g,19.32 mmol, 2.0 eq), BINAP (1.2 g, 1.93 mmol, 0.2 eq) and Pd₂(dba)₃CHCl₃(1.0 g, 0.97 mmol, 0.1 eq). The reaction mixture was stirred for 16 h at100° C. under N₂. The solvent was concentrated and the residue waspurified by silica gel flash column chromatography eluted with PetroleumEther/EtOAc (1/1) to give the desired product Example 203e (960 mg,28.7% yield) as a yellow solid. LCMS [M+1]⁺=347.3.

Step 4: Example 203

To a solution of Example 203e (860 mg, 2.48 mmol, 1.0 eq) dioxane (40mL) were added Example 203f (512 mg, 2.97 mol 1.2 eq), Cs₂CO₃ (1.62 g,4.96 mmol, 2.0 eq), BINAP (309 mg, 0.50 mmol, 0.2 eq) and Pd₂(dba)₃CHCl₃(257 mg, 0.25 mmol, 0.1 eq). The reaction mixture was stirred for 4 h at110° C. under N₂. The solvent was concentrated and the residue waspurified by silica gel flash column chromatography eluted with DCM/MeOH(20/1) to give the desired product Example 203 (425.0 mg, 35.5% yield)as an off white solid. LCMS [M+1]⁺=483.3. ¹H NMR (300 MHz, DMSO-d₆) δ12.00 (s, 1H), 10.24 (s, 1H), 9.02 (s, 1H), 8.94 (s, 1H), 8.66 (dd,J=4.8, 1.8 Hz, 1H), 8.29 (dd, J=7.8, 1.8 Hz, 1H), 7.99 (dd, J=10.8. 8.1Hz, 1H), 7.60 (dd, J=8.4, 2.1 Hz, 1H), 7.35 (dd, J=7.8. 4.8 Hz, 1H),5.25 (s, 1H), 3.34 (s, 3H), 3.09 (s, 2H).

Example A. TYK2 JH2 Domain Binding Assay

DiscoverX's KINOMEscan™ is a popular platform for kinase profiling,frequently used in academic and industry witnessed by publications,therefore we selected this platform as a primary cell-free screeningassay to determine the relative binding potency and guide chemistry SAR.

Developed by DiscoverX, KINOMEscan™ employs proprietary active-sitedependent competition binding assays to determine how compounds bind tokinases. KINOMEscan™ is based on a competition binding assay thatquantitatively measures the ability of a compound to compete with animmobilized, active site directed ligand. The assay is performed bycombining three components: DNA-tagged kinase; immobilized ligand; and atest compound. The ability of the test compound to compete with theimmobilized ligand is measured via quantitative PCR of the DNA tag.

Streptavidin-coated magnetic beads were treated with biotinylated smallmolecule ligands for 30 minutes at room temperature to generate affinityresins for kinase assays. The liganded beads were blocked with excessbiotin and washed with blocking buffer (SeaBlock (Pierce), 1% BSA, 0.05%Tween 20, 1 mM DTT) to remove unbound ligand and to reduce non-specificbinding. Binding reactions were assembled by combining TYK2(JH2domain-pseudokinase), liganded affinity beads, and test compounds in1× binding buffer (20% SeaBlock, 0.17× PBS, 0.05% Tween 20, 6 mM DTT).Test compounds were prepared as 111X stocks in 100% DMSO. All testcompounds were shipped to DiscoverX in DMSO with concentration of 10 mM.Kds were determined using an 11-point 3-fold compound dilution serieswith three DMSO control points. Each compound was tested in duplicate.All compounds for Kd measurements are distributed by acoustic transfer(non-contact dispensing) in 100% DMSO. The compounds were then diluteddirectly into the assays such that the final concentration of DMSO was0.9%. All reactions performed in polypropylene 384-well plate. Each wasa final volume of 0.02 ml. The assay plates were incubated at roomtemperature with shaking for 1 hour and the affinity beads were washedwith wash buffer (1× PBS, 0.05% Tween 20). The beads were thenre-suspended in elution buffer (1× PBS, 0.05% Tween 20, 0.5 μMnon-biotinylated affinity ligand) and incubated at room temperature withshaking for 30 minutes. The kinase concentration in the eluates wasmeasured by qPCR.

The amount of kinase measured by qPCR (Signal; y-axis) is plottedagainst the corresponding compound concentration in nM in log10 scale(x-axis). Binding constants (Kds) were calculated with a standarddose-response curve using the Hill equation:

${Response} = {{Background} + \frac{{Signal} - {Background}}{1 + \left( {{Kd}^{{Hill}{Slope}}/{Dose}^{{Hill}{Slope}}} \right)}}$

The Hill Slope was set to −1.

Curves were fitted using a non-linear least square fit with theLevenberg-Marquardt algorithm.

The results are shown in table 1.

TABLE 1 TYK2 (JH2 domain) Ex. binding Kd (nM) 1 A 2 A 3 C 4 A 5 A 6 A 7A 8 A 9 A 10 A 11 A 12 A 13 A 14 A 15 A 16 A 17 A 18 A 19 A 20 A 21 A 22A 23 A 24 B 25 A 26 A 27 A 28 A 29 A 30 A 32 A 33 A 34 A 35 A 36 A 37 A38 A 39 C 40 A 41 B 42 B 43 C 44 B 45 A 46 A 47 A 48 A 49 A 50 A 51 A 52A 53 A 54 A 55 B 56 B 57 B 58 C 59 B 60 B 61 B 62 C 63 A 64 A 65 C 66 B67 A 68 A 69 A 70 B 71 A 72 A 73 C 74 A 75 A 76 B 77 B 78 A 79 A 80 A 81A 82 A 83 A 84 A 85 A 86 A 87 A 88 A 89 A 90 A 91 A 92 A 93 A 94 A 95 A96 A 97 A 98 A 99 A 100 A 101 A 102 A 103 A 104 C 116 A 108 A 118 D 123D 126 A 127 A 145 A 147 A 159 A 163 A 166 A 195 A 200 A 198 A 199 A 202A 201 A A is less or equal than 1 nM; B is more than 1 nM and less orequal than 5 nM; C is more than 5 nM and less or equal than 10 nM; D ismore than 10 nM.

Example B: IL-12 Induced pSTAT4 in Human PBMC

Fresh Human PBMCs were resuspended in RPMI 1640 medium with 10% FBS.Cells were seeded in a round bottom 96-well plate at the concentrationof 200,000 cells/well. A 10-point dilution series of test compound (topdose 10 uM, 1:5 dilution) was added to the well using the liquiddispenser (Tecan D300e) and incubated for 1 hour at 37C. Then humanIL-12 recombinant protein (R&D Systems) was added to the well at thefinal concentration of 10 ng/ml and incubated for 15 minutes at 37C.Cell lysates were prepared and analyzed by Phospho STAT4 (Tyr693) Kit(Meso Scale Discovery) following manufacturer's protocol.

For calculation of the inhibition rate, the relative pSTAT4 signal ofeach well=pSTAT4 signal of each well the average pSTAT4 signal ofbaseline.

The inhibition %=(the average pSTAT4 signal of IL-12 treatment wells−therelative of pSTAT4 signal in each compound containing well)/the averagepSTAT4 signal of IL-12 treatment wells*100%

The curve was plotted as the inhibition % (y-axis) vs. compoundsconcentration (x-axis) and was fitted with log(inhibitor) vs. normalizedresponse—Variable slope by GraphPad Prism7.0.

Control is BMS-986165:

The results are shown in table 2.

TABLE 2 Suppression of IL12-induced p-STAT4 in human PBMC p-STAT4Relative IC₅₀ IC₅₀ Ex. (nM) to control 1 + 17.4 2 + 10.1 3 ++ 146.6 4 +15.6 5 + 20.8 6 + 4.4 7 ++ 59.8 8 + 13.7 9 + 22.9 10 + 6.4 11 + 3.6 12 +4.5 13 + 2.9 14 + 2 15 + 2.7 16 + 3.4 17 + 7.8 18 + 5.4 19 + 3 20 + 3.621 + 4.3 22 + 3.4 23 ++ 51.9 24 ++ 32.4 25 ++ 32.5 26 + 11 27 + 3 28 +3.3 29 + 10.2 30 + 1.7 31 + 4.7 32 + 9.3 33 + 10.6 34 + 6.4 36 + 44.937 + 2 39 ++ 45.4 40 ++ 46.9 41 +++ 468.6 42 ++ 147.9 43 ++++ >3039 44++ 77 47 + 10.6 48 + 2.6 49 + 5.1 50 + 21.8 51 + 4.1 52 + 5.6 54 + 3.155 ++ 260.4 56 ++ 53.8 57 +++ 208.9 59 +++ 188.6 60 ++++ >196.1 61 +++224.8 62 +++ 630.4 63 ++ 202.1 64 ++ 143.1 67 + 17.3 68 + 10.2 69 + 6.771 ++ 28.5 72 + 9.1 74 + 13.6 77 ++ 52.7 78 + 58.9 79 ++ 10.6 80 + 3.782 + 4.3 84 + 6 85 ++ 613.9 86 + 9.7 87 + 18.7 88 + 6 89 + 8 91 + 8.394 + 16.1 95 + 18 96 + 18.7 98 + 24.2 99 + 9.2 100 + 19.7 103 + 10.8 +is less or equal than 100 nM; ++ is more than 100 nM and less or equalthan 1 μM; +++ is more than 1 μM and less or equal than 10 μM; ++++ ismore than 10 μM.

Example C: INFα Induced pSTAT3 pSTAT5 in Human PBMC

Fresh Human PBMCs were resuspended in RPMI 1640 medium with 10% FBS.Cells were seeded in a round bottom 96-well plate at the concentrationof 200,000 cells/well. A 10-point dilution series of test compound (topdose 10 uM, 1:5 dilution) was added to the well using the liquiddispenser (Tema D300e) and incubated for 1 hour at 37C. Then human INFαrecombinant protein (R&D Systems) was added to the well at the finalconcentration of 5000 units/ml and incubated for 15 minutes at 37C. Celllysates were prepared and analyzed by Phospho STAT3 (Tyr705) cellularkit (Cisbio) or Phospho STAT5 (Tyr693) Kit (Meso Scale Discovery)following manufacturer's protocol.

For calculation of the inhibition rate, the relative pSTAT signal ofeach well=pSTAT signal of each well−the average pSTAT signal ofbaseline.

The inhibition %=(the average pSTAT signal of INFα treatment wells−therelative of pSTAT signal in each compound containing well)/the averagepSTAT signal of INFα treatment wells*100%

The curve was plotted as the inhibition % (y-axis) vs. compoundsconcentration (x-axis) and was fitted with log(inhibitor) vs. normalizedresponse—Variable slope by GraphPad Prism7.0.

The results are shown in table 3.

TABLE 3 p-STAT3 p-STAT5 Relative IC₅₀ IC₅₀ IC₅₀ Ex. (nM) (nM) to control1 B 6.4 2 B 2.7 3 C >61.7 4 B 19.0 5 B 13.9 6 A 10.6 7 B 18.7 8 A 8.0 9B 21.7 10 A 14.9 11 A 6.3 12 A 7.4 13 A 2.2 14 A 1.9 13 A 5.0 16 A 4.823 B 6.6 24 B 14.2 25 B 8.4 26 B 10.5 27 A 1.5 28 A 7.8 37 A 2.2 38 A4.1 39 B 14.6 40 B 14.2 41 C 575.0 42 C 224.3 43 C 135.5 44 C 374.8 49 A6.5 51 A 12.8 54 A 9.3 55 B 15.5 56 C 89.5 57 C 230.5 59 C 122.2 60D >61.7 61 C 113.5 62 C 544.7 63 B 79.9 64 B 91.6 67 B 9.4 68 A 4.5 69 A8.5 71 B 10.0 72 B 15.7 74 A 7.0 77 C 145.8 79 B 49.7 80 A 3.7 82 A 5.684 A 5.2 86 B 17.0 87 B 28.6 89 A 5.4 107 A 5.3 108 A 2.9 109 A 5.5 110A 1.5 111 A 1.4 112 A 1.8 113 A 7.7 114 A 4.7 115 A 53.8 116 A 2.8 119 A14.1 120 A 1.1 121 A 9.1 122 A 2.7 124 A 3.1 125 A 14.4 126 A 4.8 127 A10.7 128 C >1000 129 A 9.6 130 A 9.3 131 A 2.1 132 A 4.3 133 A 18.8 135C >1000 136 A 3.3 137 A 6.1 138 A 20.8 139 A 2.3 140 A 0.8 141 A 3.2 142A 4 143 A 3.8 144 A 24.2 143 A 2.5 147 A 5.8 148 A 3 149 A 2.6 150 A 9.7151 A 16.3 152 A 2.8 153 A 4.8 154 A 3.0 155 A 3.8 156 A 4.4 157 A 9.5158 A 7.2 159 A 1.6 160 A 5.5 161 A 6.1 163 A 1.7 164 A 3.9 165 B 206166 A 3.0 169 A 49.3 171 A 1.2 172 A 1.7 173 B 113.7 174 A 0.8 175 A 0.3176 A 1.8 177 A 0.4 178 A 1.2 179 A 5.8 180 A 1.3 184 A 0.8 185 A 0.3188 A 0.6 189 A 0.8 190 A 6.3 191 A 5.4 193 A 1.4 195 A 1.6 196 B 784198 A 0.3 199 A 0.2 200 A 1.9 201 A 0.2 202 A 0.3 203 A 0.7 A is less orequal than 100 nM; B is more than 100 nM and less or equal than 1 μM; Cis more than 1 μM and less or equal than 10 μM; D is more than 10 μM.

Example D: JAK1 JH2 and JAK2 JH1 Domain Binding Assay

Similar to the method for TYK2 JH2 binding described above, JAK1 JH2 andJAK2 JH1 domain binding assay was performed using DiscoverX'sKINOMEscan™, but with change of kinase domain. These assays wereperformed to compare the binding selectivity of test compounds to JAK1JH2 and JAK2 JH1 domain. The results are shown in table 4.

TABLE 4 JAK1 (JH2 domain) JAK2 (JH1 domain) Ex. binding Kd (nM) bindingKd (nM) control A C 147 A D 38 A C 116 A C 166 A C 159 A C 163 A B 195 AC 200 A C 198 A D 199 A D 202 A B 201 A B A is less or equal than 100nM; B is more than 100 nM and less or equal than 1 μM; C is more than 1μM and less or equal than 10 μM; D is more than 10 μM.

Example E: GM-CSF-Induced pSTAT5 and IL-2-Induced pSTAT5 in Human PBMCin Human PBMC

Similar to the method for IL-12 induced pSTAT4 in human PBMC describedabove, these assays were performed to check if test compounds havecross-activity to JAK1, JAK2 and JAK3 pathways in human PBMC. Theprocedure is as described with change of stimuli to 10 ng/ml of GM-CSFor 20 ng/ml of IL-2. The data are shown in Table 5.

TABLE 5 GM-CSF-induced IL-2-induced pSTAT5 Ex. pSTAT5 IC₅₀ (nM) IC₅₀(nM) control C B 195 C C 200 D C 198 C B 199 C B 202 B B 201 B B 203 C BA is less or equal than 100 nM; B is more than 100 nM and less or equalthan 1 μM; C is more than 1 μM and less or equal than 10 μM; D is morethan 10 μM.

Example F: Pharmacokenetic Studies

The pharmacokinctics of test compounds were evaluated in male C57BL/6mice, Sprague Dawley rats, Beagle dogs, and cynomolgus monkeys whenadministered via oral gavage and IV injection. The formulation for eachtest compound is summarized in the table 6. The animals were fastedovernight before administration. Plasma samples were collected predoseand at 0.5, 1, 3, 6, 9, 12, and 24 hours postdose. The samples wereanalyzed by LC/MS/MS and the concentration of test compound at eachtimepoint was determined by linear regression. Pharmacokineticparameters were calculated from the plasma concentrations using PheonixWinNonlin. The PK results were summarized in the tables 7-10.

TABLE 6 Drag formulations used for each test compound in differentspecies Route of Ex. administration Mouse Rat Dog Monkey control Oral AA A A IV B B B B 195 Oral A A A A IV C B B B 200 Oral A A A A IV C B B B198 Oral A D D IV B C C 199 Oral A D IV B C 202 Oral D A A IV C B B 201Oral A D D IV B C C 203 Oral D IV C Formulation A: 0.5% methylcelluloseFormulation B: 5% DMSO/5% Solutol/90% saline Formulation C: 10% DMSO +10% Solutol + 80% (20% SBE-β-CD) Formulation D: 10% DMSO + 10% HS-15 +40% PEG400 + 40% (30% SBE-β-CD)

TABLE 7 Pharmacokinetic parameters of test compounds in C57BL/6 mice.Route of C₀ or AUC CL(mL · administration C_(max) (h · ng · T_(1/2)T_(max) kg − 1 · Vdss Ex. and dose (ng/mL) mL⁻¹) (h) (h) F % min − 1)(L/kg) control Oral (10 4699 8871 2.96 0.25 86.7 mg/kg) I.V. (2 mg/kg)3220 2045 2.19 15.6 1.56 195 Oral (10 4295 16678 2.110 0.500 41.7 mg/kg)I.V. (2 mg/kg) 2950 7994 2.46 4.16 0.688 200 Oral (10 4193 19295 2.0100.250 85.1 mg/kg) I.V. (2 mg/kg) 2391 4475 4.62 7.35 1.5 202 Oral (101899 6395 3.27 0.500 66.6 mg/kg) I.V. (2 mg/kg) 3343 1911 0.97 17.30.785

TABLE 8 Pharmacokinetic parameters of test compounds in Sprague Dawleyrats. Route of C₀ or AUC CL(mL · administration C_(max) (h · ng · kg − 1· Vdss Ex. & dose (ng/mL mL⁻¹) T_(1/2) (h) T_(max) (h) F % min − 1)(L/kg) control Oral (5  792 ± 260 3197 ± 600  2.93 ± 1.2  1.0 ± 0.8732.6 ± 5.4 mg/kg) I.V. (1 1743 ± 276 1966 ± 166  2.42 ± 1.7 8.41 ± 0.70.933 ± 0.12 mg/kg) 195 Oral (5 1255 ± 226 7444 ± 1396  2.37 ± 0.32 1.67± 0.58 46.7 ± 8.8 mg/kg) I.V. (1 2153 ± 123 3188 ± 603  2.14 ± 0.12 4.96± 0.91 0.824 ± 0.11 mg/kg) 200 Oral (5  948 ± 43 3657 ± 684  4.22 ± 3.61.00 42.7 ± 8.0 mg/kg) I.V. (1 1033 ± 47 1714 ± 19  1.58 ± 0.21 9.42 ±0.02  1.24 ± 0.065 mg/kg) 198 Oral (5  261 ± 35 1187 ± 53  2.85 ± 2.81.00 ± 0.87 16.9 ± 0.76 mg/kg) I.V. (1 1202 ± 70 1405 ± 29  1.22 + 0.1211.8 ± 0.22  1.10 ± 0.065 mg/kg) 199 Oral (5  140 ± 32  650 ± 34  1.66 +0.37 1.33 ± 0.58 18.4 ± 1.0 mg/kg) I.V. (1  414 ± 56  705 ± 140  1.74 +0.20 23.3 ± 4.9  3.27 ± 0.87 mg/kg) 202 Oral (5  50.1 ± 11  210 ± 60 1.29 ± 0.24 4.00 ± 2.0 8.35 ± 2.4 mg/kg) I.V. (1 1975 ± 101  504 ± 580.323 ± 0.035 33.1 ± 4.0 0.653 ± 0.03 mg/kg) 201 Oral (5  185 ± 138  499± 502  1.14 ± 0.2 0.42 ± 0.14 18.7 ± 18.9 mg/kg) I.V. (1 1186 ± 116  533± 225 0.759 ± 0.60 34.3 ± 12  1.31 ± 0.42 mg/kg)

TABLE 9 Pharmacokinetic parameters of test compounds in Beagle dogsRoute of C₀ or AUC CL(mL · administration C_(max) (h · ng · kg − 1 ·Vdss Ex. & dose (ng/mL mL⁻¹) T_(1/2) (h) T_(max) (h) F % min − 1) (L/kg)control Oral (2  222 ± 46 1312 ± 579 6.21 ± 2.9 1.67 ± 0.58 35.5 ± 15mg/kg) I.V. (1  559 ± 34 1902 ± 349 4.43 ± 0.87 8.85 ± 1.7 2.27 ± 0.23mg/kg) 195 Oral (2  285 ± 285 1517 ± 1334 5.73 ± 2.02 1.33 ± 0.58 26.2 ±23.0 mg/kg) I.V. (1  185 ± 8.4 2899 ± 453 6.69 ± 0.39 5.31 ± 0.93 3.04 ±0.27 mg/kg) 200 Oral (2  247 ± 17 2619 ± 258 8.51 ± 1.6 1.33 ± 0 82.9 ±8.2 mg/kg) I.V. (0.5 29.7 ± 14  790 ± 196 11.5 ± 1.6 8.17 ± 2.6 8.37 ±1.39 mg/kg) 198 Oral (2 68.8 ± 18  253 ± 48 1.42 ± 0.24 1.67 ± 0.58 54.0± 10 mg/kg) I.V. (1  182 ± 47.6  234 ± 94 4.29 ± 1.25 68.6 ± 28 23.1 ±4.59 mg/kg) 199 Oral (2 23.4 ± 4  67.6 ± 25 1.36 ± 0.05 1.33 ± 0.6 10.7± 3.9 mg/kg) I.V. (1  334 ± 96  315 ± 188 1.78 ± 0.59 63.2 ± 30 5.62 ±1.13 mg/kg) 202 Oral (2  156 ± 53  555 ± 154 1.59 ± 0.15 1.00 55.0 ± 15mg/kg) I.V. (1  469 ± 255  504 ± 49 1.74 ± 0.28 32.7 ± 3.1 4.21 ± 0.19mg/kg) 201 Oral (2  103 ± 28  442 ± 81 5.05 ± 0.47  2.0 ± 0 38.5 ± 7.1mg/kg) I.V. (1  458 ± 336  575 ± 158 4.54 ± 1.26 29.3 ± 8.01 7.41 ± 2.64mg/kg)

TABLE 10 Pharmacokinetic parameters of test compounds in cynomolgusmonkeys (NA: no detectable) Route of C₀ or AUC CL(mL · administrationC_(max) (h · ng · kg − 1 · Vdss Ex. & dose (ng/mL mL⁻¹) T_(1/2) (h)T_(max) (h) F % min − 1) (L/kg) control Oral (2  247 ± 136  3192 ± 1629 10.6 ± 3.8 5.33 ± 1.2 27.8 ± 14 mg/kg) I.V. (1 1417 ± 264  5739 ± 1168 7.54 ± 1.6  2.79 ± 0.74  1.20 ± 0.042 mg/kg) 195 Oral (2  663 ± 497 5420 ± 3250  5.80 ± 0.73  4.0 ± 0 16.6 ± 9.95 mg/kg) I.V. (1 1286 ± 10616326 ± 664  7.65 ± 0.56 0.898 ± 0.04 0.624 ± 0.03 mg/kg) 200 Oral (2 384 ± 22  4060 ± 251  8.60 ± 0.73  2.0 ± 0 27.7 ± 1.7 mg/kg) I.V. (1 677 ± 81  7316 ± 202  9.35 ± 1.57  1.87 ± 0.21  1.45 ± 0.18 mg/kg) 198Oral (2  246 ± 124  1228 ± 435  1.28 ± 0.18   4 ± 0 59.4 ± 21.1 mg/kg)I.V. (1  667 ± 82  1034 ± 159  1.45 ± 0.22  16.1 ± 2.4  1.94 ± 0.03mg/kg) 201 Oral (2  13.9 ± 2   67.9 ± 21  3.08 ± 0.66 2.33 ± 1.5 4.67 ±1.5  23.2 ± 4.3  1.47 ± 0.1 mg/kg) I.V. (1  849 ± 50  726 ± 134  1.81 ±0.76 mg/kg) 203 Oral (2 NA NA NA NA. NA mg/kg) I.V. (1  787 ± 61  595 ±48 0.951 ± 0.22  27.6 ± 1.9 0.931 ± 0.01 mg/kg)

Example E: Pharmaceutical Compositions Example E1: ParenteralComposition

To prepare a parenteral pharmaceutical composition suitable foradministration by injection, 100 mg of a water-soluble salt of acompound described herein is dissolved in DMSO and then mixed with 10 mLof 0.9% sterile saline. The mixture is incorporated into a dosage unitform suitable for administration by injection.

Example E2: Oral Composition

To prepare a pharmaceutical composition for oral delivery, 100 mg of acompound described herein is mixed with 750 mg of starch. The mixture isincorporated into an oral dosage unit for, such as a hard gelatincapsule, which is suitable for oral administration.

Example E3: Sublingual (Hard Lozenge) Composition

To prepare a pharmaceutical composition for buccal delivery, such as ahard lozenge, mix 100 mg of a compound described herein, with 420 mg ofpowdered sugar mixed, with 1.6 mL of light corn syrup, 2.4 mL distilledwater, and 0.42 mL mint extract. The mixture is gently blended andpoured into a mold to form a lozenge suitable for buccal administration.

The examples and embodiments described herein are for illustrativepurposes only and in some embodiments, various modifications or changesare to be included within the purview of disclosure and scope of theappended claims.

What is claimed is:
 1. A compound:

or a pharmaceutically acceptable salt thereof.
 2. A compound:

or a pharmaceutically acceptable salt thereof.